Lotte Nedergaard

Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass

OBJECTIVE Diagnostic factors are needed to improve the currently used serum CA125 and risk of malignancy index (RMI) in differentiating ovarian cancer (OC) from other pelvic masses, thereby achieving precise and fast referral to a tertiary center and correct selection for further diagnostics. The aim was to evaluate serum Human Epididymis protein 4 (HE4) and the risk of ovarian malignancy algorithm (ROMA) for these purposes. METHODS Serum from 1218 patients in the prospective ongoing pelvic mass study was collected prior to diagnosis. The HE4 and CA125 data were registered and evaluated separately and combined in ROMA and compared to RMI. RESULTS 809 benign tumors, 79 borderline ovarian tumors, 252 OC (64 early and 188 late stage), 9 non-epithelial ovarian tumors and 69 non-ovarian cancers were evaluated. Differentiating between OC and benign disease the specificity was 62.2 (CA125), 63.2 (HE4), 76.5 (ROMA) and 81.5 (RMI) at a set sensitivity of 94.4 which corresponds to RMI=200. The areas under the curve (AUC) were 0.854 (CA125), 0.864 (HE4), 0,897 (ROMA) and 0.905 (RMI) for benign vs. early stage OC. For premenopausal benign vs. OC AUC were 0.925 (CA125), 0.905 (HE4), 0.909 (ROMA) and 0.945 (RMI). CONCLUSION HE4 and ROMA helps differentiating OC from other pelvic masses, even in early stage OC. ROMA performs equally well as the ultrasound depending RMI and might be valuable as a first line biomarker for selecting high risk patients for referral to a tertiary center and further diagnostics. Further improvements of HE4 and ROMA in differentiating pelvic masses are still needed, especially regarding premenopausal women.

MRI, PET/CT and ultrasound in the preoperative staging of endometrial cancer - a multicenter prospective comparative study.

OBJECTIVES The aim of this prospective multicenter study was to evaluate and compare the diagnostic performance of PET/CT, MRI and transvaginal two-dimensional ultrasound (2DUS) in the preoperative assessment of endometrial cancer (EC). METHODS 318 consecutive women with EC were included when referred to three Danish tertiary gynecological centers for surgical treatment. Preoperatively they were PET/CT-, MRI-, and 2DUS scanned. The imaging results were compared to the final pathological findings. This study was approved by the National Committee on Health Research Ethics. RESULTS For predicting myometrial invasion, we found sensitivity, specificity, PPV, NPV, and accuracy for PET/CT to be 93%, 49%, 41%, 95% and 61%, for MRI to be 87%, 57%, 44%, 92%, and 66% and for 2DUS to be 71%, 72%, 51%, 86% and 72%. For predicting cervical invasion, the values were 43%, 94%, 69%, 85% and 83%, respectively, for PET/CT, 33%, 95%, 60%, 85%, and 82%, respectively, for MRI, and 29%, 92%, 48%, 82% and 78% for 2DUS. Finally, for lymph node metastases, the values were 74%, 93%, 59%, 96%, and 91% for PET/CT and 59%, 93%, 40%, 97% and 90% for MRI. When comparing the diagnostic performance we found PET/CT, MRI and 2DUS to be comparable in predicting myometrial invasion. For cervical invasion and lymph node metastases, however, PET/CT was the best. CONCLUSIONS None of the modalities can yet replace surgical staging. However, they all contributed to important knowledge and were, furthermore, able to upstage low-risk patients who would not have been recommended lymph node resection based on histology and grade alone.

Cryopreservation of ovarian tissue for fertility preservation: no evidence of malignant cell contamination in ovarian tissue from patients with breast cancer

Cryopreserved ovarian cortical biopsies from 51 patients with breast cancer were examined by histologic and immunohistochemical analysis and showed no sign of metastases. Autotransplantation of ovarian cortex to patients with low-stage breast cancer disease appears safe, but confirmatory studies are required, including xenotransplantation studies.

IMMUNOHISTOCHEMICAL DETECTION OF METALLOTHIONEIN IN PRIMARY BREAST CARCINOMAS AND THEIR AXILLARY LYMPH NODE METASTASES

Metallothioneins (MTs) are low-molecular-weight proteins with specific binding for group II metal ions. MTs are involved in the detoxification of metals, but can also play a role in protection of the cell against certain anticancer agents and from damage of irradiation. High expression of MTs in primary breast carcinomas has been found to be associated with poorer prognosis. Expression of MT (MT) was examined immunohistochemically in 160 breast carcinomas and their concomitant lymph node metastases. The immunoreactivity appeared to be independent of the length of fixation when the section was microwaved before incubation with the primary antibody, a monoclonal antibody E-9. The findings were correlated with various histopathological factors, disease-free survival and over-all survival. Patients were divided into two groups, those with MT over-expression (above 10% of positive tumour cells), and those with low MT expression (below 10% positive). MT over-expression was found to be correlated with postmenopausal status and inversely with positive progesterone receptor status (PgR). MT over-expression showed statistically significant correlation with poor over-all survival. No differences in survival were seen between pre- and postmenopausal patients. PgR was in univariate analysis a poor prognostic parameter. In one fourth of the patients, the lymph node metastases showed increased MT expression compared with the primary tumour. These patients had a poorer, but not statistically significant different survival. MT expression was not correlated to chemo- or radiation therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Does the use of diagnostic PET/CT cause stage migration in patients with primary advanced ovarian cancer?

OBJECTIVE To investigate if the use of diagnostic FDG-PET/CT leads to stage migration in patients with advanced ovarian cancer and to evaluate the prognostic significance of FDG-PET/CT. METHODS From September 2004 to August 2007, 201 patients with a Risk of Malignancy Index (RMI) >150 based on serum CA-125, ultrasound examinations and menopausal state, underwent PET/CT within 2 weeks prior to standard surgery/debulking of a pelvic tumor. On 15 August, 2009 overall survival and prognostic variables were analysed in 66 ovarian cancer patients (64 stage III and 2 stage IV). RESULTS Median follow-up was 30.2 months; median age was 62.5 years (range 35-85 years); 97% (64/66) had a performance status <or=2; 38% (25/66) underwent complete debulking (no macroscopic residual tumor); 51% (39/66) was diagnosed with PET/CT stage III and 41% (27/66) was diagnosed with PET/CT stage IV. Survival was significantly longer for patients with PET/CT stage III than for patients with PET/CT stage IV (P=0.03). Using univariate analysis, PET/CT stage III (P=0.03), complete debulking (no macroscopic residual tumor) (P=0.002), and GOG performance status <or=2 (P=0.04) were statistically significant prognostic variables. Using multivariate Cox regression analysis, complete debulking was the only statistically significant independent prognostic variable (P=0.02). CONCLUSION In primary advanced ovarian cancer the use of diagnostic FDG-PET/CT leads to stage migration. Adequate staging is the foundation for ovarian cancer treatment and advanced imaging for optimal evaluation of metastases should be promoted in clinical trials. The strongest determinant of patient outcome is residual abdominal tumor after primary surgery.

Immunohistochemical study of estrogen receptors in primary breast carcinomas and their lymph node metastases including comparison of two monoclonal antibodies

Estrogen receptors (ER) status was investigated in 101 primary breast carcinomas and their axillary lymph node metastases to determine if the malignant cells retained or changed this phenotypic feature during the metastatic process. Immunohistochemistry with the ER‐ICA kit (Abbott Laboratory) on formalin‐fixed paraffin‐embedded tissue was used (paraffin ER‐ICA). The ER status in primary and secondary tumours was concordant in 80 patients (79%) and discordant in 21 (21%). Eighteen of these twenty‐one patients had ER‐positive primary tumours and ER‐negative lymph node metastases. This discordance, which may be due to loss of ERs in the metastatic cells or tumour heterogeneity, could explain the well‐known failure of endocrine treatment in some of the patients with ER‐positive primary tumours. A new monoclonal antibody ID5 (DAKO) against ERs was applied on formalin‐fixed paraffin‐embedded tissue from 83 of these 101 primary carcinomas. These analyses and paraffin ER‐ICA analyses were compared to prior analyses of the same 83 tumours using the ER‐ICA kit on fresh frozen tissue (“gold standard”, frozen ER‐ICA). Kappa coefficient, sensitivity and specificity were 0.74, 0.96 and 0.75 for ID5 antibody, and 0.59, 0.72 and 0.96 for ER‐ICA antibody on paraffin sections.

Standardized FDG uptake as a prognostic variable and as a predictor of incomplete cytoreduction in primary advanced ovarian cancer

Abstract Introduction. In patients with advanced ovarian cancer undergoing preoperative PET/CT, we investigated the prognostic value of SUV in the primary tumor and we evaluated the value of SUV for predicting incomplete primary cytoreduction (macroscopic residual tumor). Material and methods. From September 2004 to August 2007, 201 consecutive patients with a pelvic tumor and a Risk of Malignancy Index (RMI) > 150 based on serum CA-125, ultrasound examinations and menopausal state, underwent PET/CT within two weeks prior to standard surgery/debulking of a pelvic tumor. At two-year follow-up (August 15, 2009) the association between SUV and overall survival/cytoreductive result were analyzed in 60 ovarian cancer patients (58 stage III and two stage IV). Results. At inclusion median age was 62 years (range 35–85 years); 97% (58/60) had a performance status ≤2; 42% (25/60) underwent complete debulking (no macroscopic residual tumor); median SUVmax was 13.5 (range 2.5–39.0). Median follow-up was 30.2 months. At follow-up 57% (34/60) were alive and 43% (26/60) had died from ovarian cancer. SUVmax in patients alive was not statistically different from SUVmax in dead patients (p=0.69), and SUVmax was not correlated with the amount of residual tumor after surgery (p=0.19). Using univariate Cox regression analysis, residual tumor was a significant prognostic variable (p=0.001); SUVmax was not a statistically significant prognostic variable (p=0.86). Discussion. FDG uptake (SUVmax) in the primary tumor of patients with advanced ovarian cancer was not a prognostic variable and the FDG uptake did not predict complete cytoreduction after primary surgery. Future prospective clinical trials will need to clarify if other PET tracers can serve as prognostic variables in ovarian cancer.

Risk of malignancy index used as a diagnostic tool in a tertiary centre for patients with a pelvic mass

Abstract  Objective. Risk of malignancy index (RMI), based on a serum cancer antigen 125 level, ultrasound findings and menopausal status, is used to discriminate ovarian cancer from benign pelvic mass. In Denmark, patients with pelvic mass and RMI ≥200 are referred to tertiary gynecologic oncology centers according to the national guidelines for ovarian cancer treatment. The guidelines include recalculation of RMI at the tertiary center and, if indicated, positron emission tomography/computed tomography and fast‐track surgery by specialists in cancer surgery. The aim of this study was to validate the use of RMI ≥200 as a tool for preoperative identification of ovarian cancer at a tertiary center. Design. Prospective observational study. Setting. A tertiary center in Copenhagen, Denmark. Population. One thousand one hundred and fifty‐nine women with pelvic mass. Methods. The RMI was calculated after ultrasound examination and blood sampling for serum cancer antigen 125 analysis within two weeks before surgery. Main outcome measures. Sensitivity, specificity, positive and negative predictive values were calculated to evaluate the ability of RMI to distinguish between ovarian cancer and benign pelvic mass. Results. There were 778 women diagnosed with benign pelvic mass, while 251 had ovarian cancer and 74 had borderline ovarian tumor. Fifty‐six women were diagnosed with other forms of cancer. Sensitivity and specificity for ovarian cancer vs. benign pelvic mass for RMI ≥200 were 92 and 82%, respectively. Corresponding positive and negative predictive values were 62 and 97%. Conclusions. Risk of malignancy index ≥200 is a reliable tool for identifying patients with ovarian cancer pelvic masses at a tertiary centre to select patients for further preoperative examinations.

Interobserver agreement for tumour type, grade of differentiation and stage in endometrial carcinomas

The histopathologic evaluation plays a major role in subdividing endometrial carcinomas into treatment groups. We have evaluated the interobserver agreement regarding tumour type, grade of differentiation, stage and stage I low and high risk cases. A total of 177 cases of endometrial carcinoma in which a hysterectomy and a bilateral salpingo‐oophorectomy were performed, were reviewed by three examiners. A variety of features including tumour type, architectural grade, nuclear grade, FIGO grade, and spread/metastases were recorded, and the FIGO stage was determined. Using two different definitions low and high risk groups in stage I tumours were separated. A kappa value was calculated for each of the various parameters. The current study showed a good strength of agreement for tumour type, myometrial invasion, spread/metastases, and FIGO stage (kappa 0.62–1.00). For two of the examiners good agreement was found as to architectural grade (kappa 0.71) while the kappa value for nuclear grade was lower (0.56). As nuclear grading is included in the revised FIGO recommendation a precise definition of nuclear atypia is needed. In stage I tumours very good agreement was demonstrated as to the defined low and high risk group (Kappa 0.64–0.86).

A novel proteomic biomarker panel as a diagnostic tool for patients with ovarian cancer.

BACKGROUND Previous reports have shown that the proteomic markers apolipoprotein A1, hepcidin, transferrin, inter-alpha trypsin IV internal fragment, transthyretin, connective-tissue activating protein 3 and beta-2 microglobulin may discriminate between a benign pelvic mass and ovarian cancer (OC). The aim was to determine if these serum proteomic biomarkers alone as well as in combination with age and serum CA125, could be helpful in triage of women with a pelvic mass. METHODS We included prospectively 144 patients diagnosed with (OC), 40 with a borderline tumor and 469 with a benign tumor. Surface-enhanced laser desorption/ionization time of flight-mass spectrometry was used for analyses. The Danish Index (DK-Index) based on the proteomic data, age and CA125 was developed using logistic regression models. RESULTS Multivariate logistic regression analysis demonstrated that the selected proteomic markers, CA125 and age were independent predictors of OC and the combination of these is proposed as the DK-index. A sensitivity (SN) of 99% had a specificity (SP) of 57% for DK-index and 49% for CA125. At a SN of 95%, the SP increased to 81% for DK-index compared to 68% for CA125 alone. For stage I+II the SP was 58% for DK-index and 49% for CA125. For stage III+IV the corresponding values were 94% and 86% respectively. CONCLUSIONS The DK-index warrants further evaluation in independent cohorts.