Annika Auranen

A systematic review of gynecological cancer surveillance in women belonging to hereditary nonpolyposis colorectal cancer (Lynch syndrome) families

Objective/Design. We performed a systematic review of studies that evaluate the role of gynecological cancer surveillance in women who carry a hereditary nonpolyposis colorectal cancer (HNPCC) mutation or belong to a family that fulfills the criteria for HNPCC. Methods. The PubMed database and a clinical trials database were used to identify relevant studies. We included studies that reported results of gynecological cancer surveillance in women who carry a HNPCC mutation, belong to a family in which a HNPCC mutation was detected or belong to a family fulfilling the Amsterdam II criteria. Main Outcome Measures. Number and stage of cancers, interval cancers and cancer precursor states detected at screening. Results. Five studies fulfilled our review criteria. Surveillance modalities for endometrial cancer included transvaginal ultrasound combined with endometrial sampling when indicated, or transvaginal ultrasound with a routine endometrial biopsy, and, in certain studies, the tumor marker CA‐125. The highest yield of pathological findings in surveillance visits, from 5 to 6.5%, occurred in studies that included routine endometrial biopsies. Without a routine sampling, 7/14 cancers and 11/18 hyperplasias would have been missed. One case of advanced ovarian cancer was detected at surveillance. Conclusions. Currently available published studies on gynecological cancer surveillance in women with HNPCC do not adequately allow for evidence‐based clinical decisions. Detection of endometrial cancer or hyperplasia in nonsymptomatic women belonging to an HNPCC family is improved by adding routine endometrial sampling along with transvaginal ultrasound for surveillance visits. No benefit was shown for ovarian cancer surveillance.

Cancer incidence in the first-degree relatives of ovarian cancer patients

Cancer incidence was studied among 3072 first-degree relatives of 559 unselected ovarian cancer patients. Among cohort members there were 306 cancer cases. The overall cancer incidence was not increased: the standardised incidence ratio (SIR) in males was 0.9 (95% confidence interval 0.8-1.1) and in females 1.0 (0.8-1.1). The female relatives had a significantly increased risk for ovarian cancer (SIR 2.8, 1.8-4.2). The excess was attributable to sisters only (SIR 3.7, 2.3-5.7). The relative risk for ovarian cancer among sisters decreased both by increasing age of the sister and by increasing age at diagnosis of the index patient: the SIRs were 7.3 (1.5-21.4), 4.5 (1.6-9.8) and 3.1 (1.7-5.4) for sisters of index patients diagnosed in age < 45, 45-54 and 55-75 years respectively. The age dependency of the risk supports the role of genetic factors in familial ovarian cancer. Although the risk of ovarian cancer among sisters from families with breast cancer (SIR 9.2, 3.7-19.0) was significantly higher than among sisters from families with no breast cancer patients (SIR 2.9, 1.6-4.8, rate ratio 3.1, P < 0.05), the excess was not solely attributable to coaggregation of breast and ovarian cancer. Among the 27 families with two or more ovarian cancers, only sisters were affected in 24 families, which might implicate recessive inheritance or shared environmental factors influencing ovarian cancer risk in sisters.

Prognostic factors of ovarian granulosa cell tumor: a study of 35 patients and review of the literature.

Ovarian granulosa cell tumors (GCT) are rare tumors with a tendency of late relapse and good prognosis. FIGO stage, tumor size, degree of cellular atypia, and mitotic index have been reported to predict recurrence. The objective of this study is to evaluate treatment practice and prognostic factors of GCT. For this purpose, a detailed review of patient files and histopathologic evaluation of tumor samples, including estimation of growth pattern, presence of Call-Exner bodies, nuclear atypia, mitotic index, and immunohistochemical staining for inhibin and Ki-67 were analyzed. Thirty-five patients had histologically confirmed GCT. Four patients had a simultaneous endometrial adenocarcinoma. Median follow-up time was 135 months (range 19–334 months). Recurrent disease was detected in seven patients. Time from diagnosis to the first recurrence varied from 24 to 141 months. There was no difference in tumor size, nuclear atypia, mitotic index, presence of Call-Exner bodies, or Ki-67 staining between nonrecurred and recurred patients. The only factor associated with risk of recurrence was rupture of the tumor (P< 0.0001), and the only factor associated with overall survival was FIGO stage (P= 0.032). The disease-free and overall survivals were not statistically different between patients treated (N= 18) or not treated (N= 17) with adjuvant therapy. One patient has experienced seven recurrences, has been treated with surgery, radiation therapy, chemotherapy, and hormonal therapy, and is still alive 26 years from diagnosis. FIGO stage and tumor rupture were the only factors associated with the outcome of GCT. Treatment of relapse, even in case of multiple recurrences, is usually worthwhile.

FDG PET/CT in staging of advanced epithelial ovarian cancer: Frequency of supradiaphragmatic lymph node metastasis challenges the traditional pattern of disease spread

OBJECTIVE Epithelial ovarian cancer (EOC) spreads intra-abdominally and to the retroperitoneal lymph nodes. A greater number of distant metastases are revealed by (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) compared to conventional imaging methods. We aimed to investigate the presence and anatomic distribution of supradiaphragmatic lymph node metastasis (LNM) detected with pretreatment FDG PET/CT. METHODS Thirty women with advanced stage (IIC-IV) EOC were scanned with whole body contrast-enhanced FDG PET/CT prior to surgery/neoadjuvant chemotherapy. We performed PET/CT analysis qualitatively and quantitatively. Additionally, contrast-enhanced CT was analyzed blinded to PET/CT scan. Intra-abdominal dissemination was verified by surgery and histopathology. Metabolically active lymph nodes were biopsied when possible. The clinical characteristics of patients with and without supradiaphragmatic LNM were compared. RESULTS In 20/30 patients (67%) FDG PET/CT detected supradiaphragmatic LNM in one or more locations, whereas conventional CT found LNM in 10 patients (33%). Fourteen patients had parasternal, 14 cardiophrenic, 8 other mediastinal, 6 axillar, and 1 subclavian LNM. Microscopy of all four biopsied lymph nodes (three axillar and one subclavian) confirmed metastatic dissemination. The patients with supradiaphragmatic LNM had significantly more ascites (p<0.01), higher CA 125 levels, and more frequent subdiaphragmal carcinomatosis (p<0.03) compared to patients without supradiaphragmatic LNM in preoperative FDG PET/CT. CONCLUSIONS A significant number of patients with advanced EOC showed supradiaphragmatic LNM in pre-treatment PET/CT. Our findings suggest that the route of EOC cells from the peritoneal cavity to the lymphatic system permeates the diaphragm mainly to the cardiophrenic and continues to parasternal lymph nodes.

A prospective comparison of integrated FDG-PET/contrast-enhanced CT and contrast-enhanced CT for pretreatment imaging of advanced epithelial ovarian cancer.

OBJECTIVE The use of tumor debulking surgery in the management of epithelial ovarian cancer (EOC), which is often disseminated in the peritoneal cavity at the time of diagnosis, has a significant impact on prognosis. We compared (18)F-fluorodeoxyglucose (FDG) positron emission tomography/contrast-enhanced computed tomography (PET/CT) to contrast-enhanced CT for the detection of dissemination into the abdominal cavity preventing successful primary debulking surgery. METHODS Forty-one women with EOC underwent preoperative whole-body low-dose FDG-PET/CT followed by diagnostic high dose contrast-enhanced CT scan, and the results were compared with systematically recorded surgical findings as a reference standard. Both site-based and patient-based analyses were conducted. RESULTS FDG-PET/CT was superior to conventional CT for the detection of carcinomatosis in subdiaphragmatic peritoneal surfaces (p=0.020) and in the bowel mesentery (p=0.001). Patient-based analysis of upper abdominal areas requiring extensive surgical procedures showed no significant differences between the two imaging methods. The sensitivity of PET/CT and CT was poor in certain areas of the peritoneal cavity (64% vs. 27% in the small bowel mesentery and 65% vs. 55% in the right upper abdomen). Extra-abdominal disease spread was detected by PET/CT in 32 patients and by CT in 25 patients. CONCLUSIONS PET/CT was not superior to CT for the detection of intra-abdominal disease spread. Patients with suspected EOC should be referred for upfront radical surgery regardless of the results of preoperative imaging studies. PET/CT is more effective for the detection of extra-abdominal disease than CT, but the clinical significance of this finding is unclear.

Is perioperative visual estimation of intra-abdominal tumor spread reliable in ovarian cancer surgery after neoadjuvant chemotherapy?

OBJECTIVE Most cases of epithelial ovarian cancer (EOC) are diagnosed in an advanced stage. When the disease has spread intra-abdominally, complete surgical tumor debulking is the single most important prognostic factor. Neoadjuvant chemotherapy (NACT) before surgery can cause fibrosis and adhesions in the peritoneal cavity and may interfere with the perioperative evaluation of tumor spread. In this prospective study, we evaluated whether perioperative visual assessment of tumor dissemination is similar in patients undergoing primary and interval surgery for EOC. METHODS Systematic visual evaluation of tumor spread was performed at the start of primary surgery/diagnostic laparoscopy (n=39) or interval surgery (n=16). Peritoneal cavity was divided into 22 anatomical regions. The carefully documented results of the visual assessment were compared with the histopathological analysis of 220 biopsies from primary and 92 biopsies from interval surgery. RESULTS In primary surgery, perioperative visual estimation of tumor spread showed 98% sensitivity, 76% specificity and 95% accuracy compared to histopathology. The corresponding figures after NACT were 86%, 76% and 84%, respectively. The difference in sensitivity and accuracy in primary and interval operations was statistically significant (p<0.001). CONCLUSIONS In advanced EOC, microscopically carcinomatous areas have a benign visual appearance more often after NACT than at primary surgery. NACT may interfere with the perioperative visual evaluation of tumor spread and thus lead to incomplete resection of tumor in potentially resectable areas.

Serum HE4 Profile During Primary Chemotherapy of Epithelial Ovarian Cancer

Objective Human epididymis protein 4 (HE4) is a promising novel serum biomarker for the detection of early-stage epithelial ovarian cancer (EOC) and for the differential diagnosis between benign and malignant ovarian tumors. The objective of the present study was to determine the value of HE4 for monitoring the response to primary therapy in patients with advanced disease. Methods Serum HE4 and cancer antigen (CA) 125 levels of 10 patients with advanced EOC and one patient with adenocarcinoma of unknown origin were measured preoperatively and during first-line chemotherapy. Seven patients were treated with primary surgery and six cycles of chemotherapy. Response to treatment was evaluated 4 weeks after the completion of chemotherapy using computed tomography. Four patients received neoadjuvant chemotherapy (NACT) before surgery. To evaluate the early response to chemotherapy, changes in serum biomarker levels were compared with metabolic changes of tumors during NACT as detected by positron emission tomography/computed tomography. Results The profile of HE4 during primary chemotherapy was in line with radiologic and clinical responses. In the neoadjuvant chemotherapy group, HE4 correlated better with the radiologic response than CA 125. Conclusion Assessment of serum HE4 may improve the reliability of response evaluation during chemotherapy for serous epithelial ovarian cancer.

Immunohistochemically detected p53 and HER-2/neu expression and nuclear DNA content in familial epithelial ovarian carcinomas.

Some epithelial ovarian carcinomas tend to occur more frequently in certain families. This clustering may be due to a genetic predisposition, but the role of inherited susceptibility in all families with multiple cases of ovarian carcinoma is currently unresolved. Studies characterizing familial ovarian carcinomas are few.

18F-FDG-PET/CT can identify histopathological non-responders to platinum-based neoadjuvant chemotherapy in advanced epithelial ovarian cancer.

OBJECTIVE The aim of this study was to examine the relationship between the reduction of maximum standardized uptake values (SUVmax) in 18F-FDG-PET/CT to histopathological changes obtained with neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian cancer (EOC). We wanted to evaluate whether 18F-FDG-PET/CT is useful for identifying patients who will not respond to NACT and would therefore benefit from second-line chemotherapy instead of interval debulking surgery (IDS). METHODS Twenty-six primarily inoperable EOC patients treated with NACT were enrolled in this study. 18F-FDG-PET/CT imaging was performed before diagnostic laparoscopy and after three to four NACT cycles. The relationship between the decrease in omental SUVmax from before to after NACT with omental histopathological response was examined in samples taken from the corresponding anatomical sites during IDS. Patients were divided into three groups according to chemotherapy-induced histopathological changes. Serum CA125 and HE4 halftimes during NACT as well as Ki-67 antigen expression in IDS samples were determined. RESULTS The median omental SUVmax change during NACT was -64% (range-16% to -84%), and it was associated with histopathological response (p=0.004, OR 0.9, CI 0.84-0.97). A SUVmax decrease of less than 57% identified histopathological non-responders. Progression-free survival (PFS) differed between the poor, moderate and good histopathological response groups (0.9 year vs. 1.2 years vs. 1.4 years, respectively, p=0.05). The SUVmax change was not associated with PFS. CONCLUSION 18F-FDG-PET/CT was able to identify patients who would not respond to NACT. To obtain a histopathological response in EOC, a substantial metabolic response in 18F-FDG-PET/CT is necessary.

Progesterone receptor negativity is an independent risk factor for relapse in patients with early stage endometrioid endometrial adenocarcinoma

OBJECTIVE In endometrioid endometrial adenocarcinoma (EEA), the currently established prognostic factors in clinical guidelines are stage and grade. Many guidelines include lymphovascular invasion (LVI) and tumor size as prognostic factors. Although several studies have associated lack of estrogen (ER) and progesterone receptor (PR) expression with reduced outcome, the prognostic use of these markers is uncommon. Better prognostication of clinical behavior would be useful in patients with early stage (I-II) disease. In this study we evaluated ER and PR as prognostic factors in EEA, and compared their expression with other potential biomarkers and clinical parameters. METHODS Tissue microarrays were constructed from 182 patients with stages I-II EEA. ER, PR, p53, Ki-67, PTEN, MLH and HER-2 expression were assessed by immunohistochemical staining and HER-2 was confirmed with SISH. The results were correlated with clinicopathologic parameters and to disease-free survival. RESULTS Eleven patients (6%) developed recurrent disease during a median follow up time of 62.8 months. In univariate analysis FIGO grade (p=0.019), positive expression of p53 (p=0.010) and negative PR expression (p=0.001) were associated with a shorter disease-free survival. In multivariate analysis only negative PR expression (p=0.019) was significantly associated with a shorter disease-free survival. LVI and tumor size where not of prognostic value. CONCLUSIONS Lack of PR expression is a strong, independent risk factor for tumor recurrence in patients with stages I-II endometrioid endometrial cancer. The use of this easily measurable biomarker as a prognostic factor in the clinical context should be considered and tested in a larger patient population.