Nicotinamide N-methyltransferase overexpression may be associated with poor prognosis in ovarian cancer.

Ovarian cancer is the fifth leading cause of cancer-related mortality in women. Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme and there is growing evidence to suggest that it plays an important role in cancer progression. This is the first study to examine the expression of NNMT in serous ovarian cystadenomas, serous borderline tumours, low grade serous carcinomas (LGSC) and high grade serous carcinomas (HGSC) and investigate the potential independent association of NNMT expression with survival. Tissue samples were analysed immunohistochemically for NNMT expression. The stromal NNMT score was significantly higher in HGSC compared to serous cystadenomas and serous borderline tumours (p < .001, p < .043, respectively). The mean stromal NNMT score of patients with HGSC was significantly higher than patients with LGSC (p = .043). Patients with low expression of NNMT had a significantly higher mean recurrence-free survival than patients with high expression (p = .036). NNMT may support tumour progression in ovarian cancer by promoting desmoplastic stromal tumour reaction. NNMT overexpression may be associated with poor prognosis and can be a therapeutic target in ovarian cancer.IMPACT STATEMENTWhat is already known on this subject? Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that is overexpressed in many malignancies. Its overexpression was shown to lead to histone hypomethylation, which in turn can decrease and increase the expression of tumour suppressor proteins and onco-proteins, respectively. NNMT was also shown to play a role in epithelial-to-mesenchymal transition, which is critical in tumour progression and the stromal tumour reaction. The stromal tumour reaction was recently targeted with promising therapeutic results in ovarian cancer.What do the results of this study add? The expression of NNMT in various ovarian neoplasms including serous cystadenomas, borderline tumours and serous carcinomas has not been studied and independently associated with poor survival, previously. This study suggests that NNMT is progressively overexpressed in the stroma of ovarian neoplasms from benign cysts to HGSCs. NNMT overexpression appears to be independently associated with poor survival in ovarian cancer.What are the implications of these findings for clinical practice and/or further research? The implications of these findings are that NNMT may play an important role in the stromal tumour reaction, and therefore its overexpression may contribute to poor survival. NNMT overexpression may be an important target of ovarian cancer therapy.

Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas).

OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1-20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. TRIAL REGISTRATION NUMBER: IRB 00006477.

Pancreatic surgery for tumors in children and adolescents.

PURPOSE: Pancreatic neoplasms are uncommon in children. This study sought to analyze the clinical and pathological features of surgically resected pancreatic tumors in children and discuss management strategies. METHODS: We conducted a retrospective review of patients ≤21 years with pancreatic neoplasms who underwent surgery at a single institution between 1995 and 2015. RESULTS: Nineteen patients were identified with a median age at operation of 16.6 years (IQR 13.5-18.9). The most common histology was solid pseudopapillary neoplasm (SPN) (n = 13), followed by pancreatic neuroendocrine tumor (n = 3), serous cystadenoma (n = 2) and pancreatoblastoma (n = 1). Operative procedures included formal pancreatectomy (n = 17), enucleation (n = 1) and central pancreatectomy (n = 1). SPNs were noninvasive in all but one case with perineural, vascular and lymph node involvement. Seventeen patients (89.5 %) are currently alive and disease free at a median follow-up of 5.7 (IQR 3.7-10.9) years. Two patients died: one with metastatic insulinoma and another with SPN who developed peritoneal carcinomatosis secondary to a concurrent rectal adenocarcinoma. CONCLUSIONS: Pediatric pancreatic tumors are a heterogeneous group of neoplastic lesions for which surgery can be curative. SPN is the most common histology, is characterized by low malignant potential and in selected cases can be safely and effectively treated with a tissue-sparing resection and minimally invasive approach.

A pancreaticoduodenectomy risk model derived from 8575 cases from a national single-race population (Japanese) using a web-based data entry system: the 30-day and in-hospital mortality rates for pancreaticoduodenectomy.

OBJECTIVE: To create a mortality risk model after pancreaticoduodenectomy (PD) using a Web-based national database system. BACKGROUND: PD is a major gastroenterological surgery with relatively high mortality. Many studies have reported factors to analyze short-term outcomes. SUBJECTS AND METHODS: After initiation of National Clinical Database, approximately 1.2 million surgical cases from more than 3500 Japanese hospitals were collected through a Web-based data entry system. After data cleanup, 8575 PD patients (mean age, 68.2 years) recorded in 2011 from 1167 hospitals were analyzed using variables and definitions almost identical to those of American College of Surgeons-National Surgical Quality Improvement Program. RESULTS: The 30-day postoperative and in-hospital mortality rates were 1.2% and 2.8% (103 and 239 patients), respectively. Thirteen significant risk factors for in-hospital mortality were identified: age, respiratory distress, activities of daily living within 30 days before surgery, angina, weight loss of more than 10%, American Society of Anesthesiologists class of greater than 3, Brinkman index of more than 400, body mass index of more than 25 kg/m, white blood cell count of more than 11,000 cells per microliter, platelet count of less than 120,000 per microliter, prothrombin time/international normalized ratio of more than 1.1, activated partial thromboplastin time of more than 40 seconds, and serum creatinine levels of more than 3.0 mg/dL. Five variables, including male sex, emergency surgery, chronic obstructive pulmonary disease, bleeding disorders, and serum urea nitrogen levels of less than 8.0 mg/dL, were independent variables in the 30-day mortality group. The overall PD complication rate was 40.0%. Grade B and C pancreatic fistulas in the International Study Group on Pancreatic Fistula occurred in 13.2% cases. The 30-day and in-hospital mortality rates for pancreatic cancer were significantly lower than those for nonpancreatic cancer. CONCLUSIONS: We conducted the reported risk stratification study for PD using a nationwide surgical database. PD outcomes in the national population were satisfactory, and the risk model could help improve surgical practice quality.

Recurrence patterns of advanced ovarian, fallopian tube, and peritoneal cancers after complete cytoreduction during interval debulking surgery.

OBJECTIVES: Similar to primary debulking surgery, complete resection of all macroscopic diseases during interval debulking surgery (IDS) is the primary objective while using neoadjuvant chemotherapy followed by IDS for advanced ovarian, fallopian tube, and peritoneal cancers. However, most patients develop recurrent disease even after complete cytoreduction during IDS. This study aims to identify recurrence patterns of the ovarian, fallopian tube, and peritoneal cancers in patients who underwent complete cytoreduction during IDS. METHODS: We retrospectively reviewed data of patients with stage III or IV ovarian, fallopian tube, and peritoneal cancers who were treated at our hospital from January 1, 2005, to December 31, 2011. RESULTS: In this study, 105 patients underwent neoadjuvant chemotherapy followed by IDS and achieved complete cytoreduction. The median follow-up period was 42.1 months. Recurrence was documented in 70 patients (66.7%), and 35 (33.3%) showed no evidence of disease. Peritoneal dissemination was the most common recurrence (60.0%) observed. In multivariate analysis, positive peritoneal cytology (P = 0.0003) and elevated pre-IDS serum CA125 levels (P = 0.046) were independent risk factors for recurrence. CONCLUSIONS: After complete cytoreduction during IDS in patients with stage III or IV ovarian, fallopian tube, and peritoneal cancers, positive peritoneal cytology at IDS and elevated pre-IDS CA125 levels are associated with an increased risk of cancer recurrence. Positive peritoneal cytology during IDS is a particularly strong predictive factor for poor outcomes in these patients.

BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer.

BACKGROUND: Low-grade serous (LGS) ovarian cancer is a chemoresistant disease that accounts for 10% of serous ovarian cancers. Prior studies have reported that 28% to 35% of serous borderline (SB)/LGS ovarian tumors harbor a BRAF mutation, suggesting that BRAF inhibitors may be a rational therapeutic approach for this disease. In the current study, the authors sought to determine whether BRAF or KRAS mutation status was associated with disease stage and/or histology in patients with SB and LGS ovarian cancer. METHODS: Genetic profiles were constructed for 75 SB and LGS ovarian tumors to determine BRAF and KRAS mutation status. The incidence and identity of BRAF and KRAS mutations were defined, and the results were correlated with disease stage, response to treatment, and overall survival. RESULTS: Of 75 samples examined, 56 tumors (75%) had SB histology, and 19 tumors (25%) had LGS histology. Fifty-seven percent of tumors harbored either a KRAS mutation (n = 17) or a BRAF mutation (a valine-to-glutamate substitution at residue 600 [V600E]; n = 26). The BRAF V600E mutation was associated significantly with early disease stage (stage I/II; P < .001) and SB histology (P = .002). KRAS mutations were not associated significantly with disease stage or histology. Of the 22 patients (29%) who required chemotherapy, 20 had tumors with wild-type KRAS/BRAF, 2 had KRAS mutant tumors, and none had tumors that harbored a BRAF mutation. All patients with BRAF tumors remained alive at a median follow-up of 3.6 years (range, 1.9-129.3 months). CONCLUSIONS: V600E BRAF mutations were present in 35% of patients who had SB/LGS ovarian cancers. The presence of the BRAF V600E mutation in SB/LGS ovarian cancer was associated with early stage disease and improved prognosis. The authors concluded that patients with SB/LGS ovarian cancer who require systemic therapy are unlikely to have BRAF mutant tumors.

Body mass index as a prognostic factor in epithelial ovarian cancer and correlation with clinico-pathological factors.

OBJECTIVE: To find out if body mass index (BMI) was associated with clinico-pathological features and prognosis in epithelial ovarian cancer (EOC). DESIGN: Retrospective cohort study. SETTING: Patients with EOC, who underwent primary surgery and postoperative chemotherapy in the Orebro Medical Region, Sweden, 1994-2003. SAMPLE: A total of 446 patients with stage I-IV EOC, who underwent primary surgery and chemotherapy with information of values of height and weight at the start of chemotherapy were eligible. METHODS: Patients were stratified by BMI according to guidelines set forth by the World Health Organization. Pearson's chi-squared test was used for univariate analyses. The level of statistical significance was p < 0.05. MAIN OUTCOME MEASURES: The survival curves were generated by using the Kaplan-Meier method, and in multivariate analyses the Cox regression model was used with cancer-specific survival as the end point. RESULTS. Of the patients, 5% were underweight (BMI < 18.5), 55% were of ideal body weight (BMI 18.5-25), 25% were overweight (BMI 25-30) and 15% were obese (BMI > 30). Among patients with serous tumors a significant (p = 0.01) worse survival was found in the subgroup of underweight (BMI < 18.5) patients compared with patients in the other BMI groups. In multivariate analysis only FIGO-stage and age were independent and significant prognostic factors. CONCLUSION: Overweight and obese patients did not have worse survival than normal weight and underweight patients. The prognostic impact of BMI on survival was only noted for underweight patients with serous tumors.

Effect of cigarette smoking on epithelial ovarian cancer survival.

OBJECTIVE: To determine associations between smoking and survival in patients with ovarian cancer. STUDY DESIGN: We performed a retrospective review of patients undergoing surgery for ovarian cancer. Abstracted patient data included age, smoking history, stage, grade, extent of cytoreduction, and survival. Data were examined with Fisher's exact test, Kaplan-Meier survival analysis, and Cox regression analysis. RESULTS: A total of 130 patients met criteria for review. Seventeen (13%) smoked cigarettes at the time of initial laparotomy. Twenty-one (16%) were left with > 1 cm residual disease. Smoking did not correlate with the incidence of suboptimal cytoreduction. There were no statistical differences in incidence of hypertension, obesity, or coronary artery disease in smokers compared to nonsmokers. Smoking was found to negatively influence length of progression-free survival. Similarly, smokers were found to have decreased disease-specific overall survival compared to nonsmokers. Cigarette smoking retained independent significance as poor prognostic factors, after controlling for age, stage, and grade. CONCLUSION: These findings identify a negative correlation with cigarette smoking and survival in women with ovarian cancer. Further studies are proposed to elucidate the molecular mechanisms underlying these clinical observations.

Clinical significance of c-Met and phospho-c-Met (Tyr1234/1235) in ovarian cancer.

OBJECTIVE: c-Met is expressed in human ovarian cancer tissues, and its phosphorylation activates signaling cascades that might affect the behavior of cancer cells. In this study, we evaluated the association of c-Met and phosphorylated c-Met (phospho-c-Met) expressions with the clinical outcomes of ovarian cancer patients. MATERIALS AND METHODS: Archived tissue from surgical specimens of 269 ovarian cancer patients who underwent a debulking operation in MacKay Memorial Hospital between 2004 and 2012 were collected. Tissue microarrays were stained with anti-Met and anti-phospho-Met (Tyr1234/1235) monoclonal antibodies. Immunostaining intensity was scored on a scale of 0-3+. High expression was defined as more than 50% of moderate and intense staining. Patients' clinical data were reviewed until April 2017 for analysis. RESULTS: The proportion of high c-Met expression was significantly higher in patients with cancer in early stages (Federation of Gynecology and Obstetrics stages I and II) and low histologic grades (grades 1 and 2) (79.70%, p = 0.0008 and 80.15%, p ≤ 0.0001, respectively). However, no association was found between phospho-c-Met and FIGO stage or the histologic grade. Ovarian clear cell carcinoma and mucinous carcinoma had much higher c-Met expression (95.16% and 87.10%, p ≤ 0.0001 and p = 0.0292, respectively). Although the overall survival did not differ significantly, low expressions of c-Met and phospho-c-Met were obviously associated with poor progression-free survival respectively (p = 0.0034, HR: 0.5264, 95% CI: 0.3326-0.8330 and p = 0.0136, HR: 0.5626, 95% CI: 0.3709-0.8535). CONCLUSION: Low c-Met expression was associated with poor clinical outcomes.

Estrogen and progestin regulate metastasis through the PI3K/AKT pathway in human ovarian cancer.

Estrogen and progestin are involved in ovarian carcinogenesis. Change in nm23-H1 expression and the PIK3/AKT pathway are involved in carcinogenesis, development, invasion and metastasis of ovarian cancers. Therefore, it is critical to understand the signaling pathways that regulate hormone-induced cell migration and invasion in ovarian cancer. We investigated nm23-H1, AKT and pAKT expression by using immunohistochemical staining in ovarian clear cell adenocarcinoma, ovarian benign, borderline and malignant serous tumors and analyzed their relationship with prognostic factors. Using ES-2 and SKOV-3 ovarian cancer cell lines, we studied the modulation of estrogen and progestin on cell migration and invasion as well as their effect on AKT, pAKT and nm23-H1 expression. Furthermore, the signaling pathways were examined using pharmacological inhibitors (LY294002 and PD98059) or AKT siRNA combined with estrogen or progestin in the two cell lines. Weak nm23-H1 and high AKT and pAKT expression was observed in ovarian serous adeno-carcinoma and ovarian clear cell adenocarcinoma. Our data demonstrated that the expression of nm23-H1 was negatively correlated with tumor stage and grade and lymph node metastasis, whereas the expression of AKT/pAKT was positively correlated with these clinic factors. Estrogen up-regulated pAKT expression and reduced nm23-H1 expression, which ultimately resulted in increased cell migration and invasion. In contrast, progestin reduced pAKT expression and increased nm23-H1 expression, which inhibited cell migration. PIK3 kinase inhibitor LY294002 antagonized the effect of estrogen. On the other hand, it reinforced the effect of progestin. Our data suggest that AKT and pAKT are unfavorable prognostic factors for ovarian serous adenocarcinoma and clear cell carcinomas whereas nm23-H1 expression predicates favorable patient prognosis. Estrogen down-regulates nm23-H1 expression and promotes cell migration and invasion by activating the PIK3/AKT pathway. Progestin has an opposing effect.

[Five years survival in patients with endometrioid ovarian cancer versus patients with serous ovarian cancer].

AIM: The ovarian cancer is the most malignant disease from all oncogynecological localizations. There are different scientific opinions whether the different histological types have different prognosis and survival. The aim of our research work was to evaluate if the endometrioid cancer of the ovary has a different prognosis from the serous ovarian cancer. METHODS: 84 patients were evaluated for five years period from 2003 till 2008. The patients with endometrioid ovarian cancer (42) were matched with the patients with serous ovarian cancer (42). They were matched for age, grading,stage, and level of cytoreduction. RESULTS: 84 patients (42 with endometrioid cancer and 42 with serous ovarian cancer) were evaluated for 5 years period. The five years survival of the patients with endometrioid ovarian cancer was 62% while the five years survival for patients with serous ovarian cancer was 72%. In patients with endometrioid ovarian cancer the mean survival rate was 58 months, and for patients with serous ovarian cancer 70 months (P=0.30). The estrogen receptor levels were not statistically significant between the two groups (P=0.110), while the progesteron receptor levels were statistically different (P<0.002). CONCLUSIONS: In patients with endometrioid and serous ovarian cancer, while taking into consideration the age, grading, stage and level of cytoreduction--there is no difference for the five years survival or the length of survival.

Prognostic significance of extracellular matrix metalloproteinase inducer and matrix metalloproteinase 2 in epithelial ovarian cancer.

AIMS: We investigated the prognostic significance of extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase 2 (MMP-2) in epithelial ovarian cancer as well as their relation to hyaluronan (HA) expression. METHODS: The expression of EMMPRIN and MMP-2 was analyzed immunohistochemically in 295 primary epithelial ovarian cancer patients and 67 metastases. RESULTS: A low membranous EMMPRIN expression was detected more often in serous tumors than in other types (p < 0.0005) and it was associated with tumors of advanced stage (p = 0.012) or with a large primary residual (p = 0.011). A low expression of MMP-2 in cancer cells was associated with a high histologic grade (grade 3) of the tumor (p = 0.005) and endometrioid type of tumors (p < 0.0005). Stromal MMP-2 expression was significantly associated with strong stromal HA expression (p = 0.002, r = 0.187). In univariate analysis, 10-year disease-related (DRS) and recurrence-free survivals were significantly better when MMP-2 expression in cancer cells was high (p = 0.0057 and p = 0.0467, respectively). DRS was also better when membranous EMMPRIN expression was high (p = 0.013). In multivariate analysis, strong MMP-2 in cancer cells (RR = 1.48, CI = 1.07-2.04, p = 0.017) indicated favorable DRS. CONCLUSION: Our results show that EMMPRIN and MMP-2 in cancer cells are significant indicators of a favorable prognosis of epithelial ovarian cancer.

Stage III endometrial cancer: preoperative predictability, prognostic factors, and treatment outcome.

OBJECTIVE: The survival rate for the most common gynecologic cancer, endometrial cancer, has fallen significantly in the last 25 years. Stage III (International Federation of Gynecology and Obstetrics) disease accounts for most of the deaths. We evaluated prognostic factors, treatment-related survival, and routinely used assessments for identifying stage III disease before the operation. STUDY DESIGN: The data for patients with endometrial cancer stage III (n = 101) who had been treated at the McGill University Health Center between 1989 and 2003 were analyzed. RESULTS: Stage IIIA, IIIB, and IIIC tumors accounted for 63%, 4%, and 33% of the data, respectively. The cause-specific survival at 2, 3, and 5 years was 82%, 77%, and 67%, respectively. In multivariate analysis with an adjustment for the standard prognostic variables, the final tumor grade, adnexal involvement, and lymph node dissection were significant predictors of cause-specific survival (P = .001, .028, and .017, respectively). Of the preoperative investigations, an elevated CA-125 level was a significant predictor of cause-specific survival in multivariate analysis (P = .029). CONCLUSION: An elevated CA-125 level, adnexal involvement, the final tumor grade, and lymph node dissection were independent predictors for cause-specific survival.

Long-term Behavior of Serous Borderline Tumors Subdivided Into Atypical Proliferative Tumors and Noninvasive Low-grade Carcinomas: A Population-based Clinicopathologic Study of 942 Cases.

Ovarian serous borderline tumors (SBTs) have been the subject of considerable controversy, particularly with regard to terminology and behavior. It has been proposed that they constitute a heterogenous group of tumors composed, for the most part, of typical SBTs that are benign and designated "atypical proliferative serous tumor (APST)" and a small subset of SBTs with micropapillary architecture that have a poor outcome and are designated "noninvasive low-grade serous carcinoma (niLGSC)". It also has been argued that the difference in behavior between the 2 groups is not due to the subtype of the primary tumor but rather the presence of extraovarian disease, specifically invasive implants. According to the terminology of the 2014 WHO Classification, typical SBTs are equivalent to APSTs and SBTs displaying micropapillary architecture are synonymous with niLGSC. In addition, "invasive implants" were renamed "low-grade serous carcinoma" (LGSC). The argument as to whether it is the appearance of the primary tumor or the presence of extraovarian LGSC that determines outcome remains unsettled. The current study was initiated in 2004 and was designed to determine what factors were predictive of outcome, with special attention to the appearance of the primary tumor (APST vs. niLGSC) and that of the extraovarian disease (noninvasive vs. invasive implants). Our study is population based, involving the entire female population of Denmark. None of the women in the study were lost to follow-up, which ranged up to 36 years (median, 15 y). All the microscopic slides from the contributing hospitals were rereviewed by a panel of 2 pathologists (R.V. and R.J.K.) who were blinded to the follow-up. After excluding those that were not SBTs by the pathology panel, as well as cases with a prior or concurrent cancer or undefined stage, 942 women remained, of which 867 were APSTs and 75 were niLGSCs. The median patient age was 50 years (range, 16 to 97 y). Eight hundred nine women (86%) presented with FIGO stage I disease, whereas 133 (14%) had advanced stage disease. Compared with APSTs, niLGSC exhibited a significantly greater frequency of bilaterality, residual gross disease after surgery, microinvasion/microinvasive carcinoma, advanced stage disease, and invasive implants at presentation (P-values <0.003). Because the cause of death is difficult to accurately ascertain from death certificates, we used development of invasive serous carcinoma as the primary endpoint as following development of carcinoma, the mortality is very high. In the entire cohort, subsequent development of carcinoma occurred in 4%, of which 93% were low grade and 7% high grade (median time, 10 y; range, up to 25 y). After adjusting for age at and time since diagnosis of APST or niLGSC, occurrence of subsequent carcinoma was significantly higher with niLGSC than APST among all stages combined (hazard ratio [HR]=3.8; 95% confidence interval [CI], 1.7-8.2). This difference was still significant for stage I but not advanced stage cases. Moreover, all-cause mortality was not statistically significantly different between APST and niLGSC. Of all women with advanced stage disease, 114 (86%) had noninvasive implants, whereas 19 (14%) were invasive. Noninvasive implants were significantly associated with subsequent development of carcinoma (HR=7.7; 95% CI, 3.9-15.0), but the risk with invasive implants was significantly higher (HR=42.3; 95% CI, 16.1-111.1). In conclusion, although invasive implants are the most important feature in predicting an adverse outcome, subclassification into APST and niLGSC is important as it stratifies women with respect to risk for advanced stage disease and invasive implants for all women and development of serous carcinoma for stage I cases.

Autoimplants in serous borderline tumors of the ovary: a clinicopathologic study of 30 cases of a process to be distinguished from serous adenocarcinoma.

The clinical and pathologic features of serous borderline tumors (SBTs) with autoimplants (AIs) were studied with emphasis on their relation to survival, ovarian SBT with a micropapillary pattern, and their distinction from serous adenocarcinoma. The 30 patients ranged in age from 17 to 70 years (mean, 35.8 years). Two had stage I disease, 10 had stage II disease, and 18 had stage III disease. Twenty-five patients had bilateral ovarian tumors. In 28 cases, AIs were present on the surface of the neoplasm or between exophytic surface tumor papillae; in 2 cases, AIs were between papillae within intracystic tumor. The AIs consisted of single cells or glands and clusters of cells with mild to moderate nuclear atypia within a fibroblastic stroma; the stroma dominated over the epithelium in extent within the AI. In many cases, the epithelial cells in the AI had abundant eosinophilic cytoplasm. All but 2 of the patients had coexisting noninvasive peritoneal implants; 3 of them also had invasive peritoneal implants. Six of the SBTs had a micropapillary pattern; 3 of these were stage III and 3 stage II tumors. Clinical follow-up was available for 11 patients. Eight were alive and well after 4 to 7 years (mean, 5 years); 3 of these patients had stage II disease and 5 had stage III disease. Three were dead of disease after 7 to 12 years (mean, 9 years). Two patients who died of disease had stage III disease, and 1 of them had invasive implants. The third patient had stage II disease, invasive implants, and the tumor was of the micropapillary type. Our study indicates that the majority of patients with SBT with AI have stage II or III disease and abundant exophytic tumor. SBTs with AI had a micropapillary pattern in 20% of the cases. AIs do not appear to have an adverse impact on survival when controlled for peritoneal implant type and for this reason must be distinguished from true stromal invasion in serous carcinoma, a misdiagnosis sometimes made, or seriously entertained, initially in these cases. Features that favor AI over carcinoma arising in an SBT are 1) a location between tumor papillae or on the ovarian surface 2) a predominance of stroma over epithelial cells, and 3) the "borderline" cytologic appearance of epithelial cells.

DEF6 expression in ovarian carcinoma correlates with poor patient survival.

BACKGROUND: Increased expression of DEF6 is correlated with the malignant behavior of various cancers. Both DEF6 and p16 contribute to the regulation of cell cycle progression, and p53 plays important role in the cell cycle checkpoints. This study was designed to elucidate the prognostic significance of DEF6, p53 and p16 immunoexpressions in different histology subtypes of ovarian carcinoma. METHODS: Immunohistochemistry results of DEF6, p53 and p16 on ovarian carcinoma were compared with histology subtypes, clinical data, overall survival (OS) and disease-free survival (DFS) by Cox regression and Kaplan-Meier analysis. RESULTS: We studied 180 cases of ovarian carcinomas (75 high-grade serous, 41 clear cell, 36 mucinous and 28 endometrioid), including 109 FIGO stage I-II cases and 71 FIGO stage III-IV cases. Ovarian carcinomas positive for both DEF6 and p16 expression were associated with the worst OS (P = 0.027) and DFS (P = 0.023), whereas those negative for both DEF6 and p16 had the best OS and DFS. Aberrant p53 expression combined with positive DEF6 was associated with worst OS (P = 0.031) and DFS (P = 0.028). Kaplan-Meier analysis showed that significantly shorter survival rates were seen in patients with high expressions of DEF6 (P = 0.008) and p16 (P = 0.022). Patients with aberrant p53 expression in high-grade serous carcinoma (P = 0.012) and patients with high DEF6 expression in clear cell carcinoma (P = 0.001) were also associated with shorter overall survival. In univariate analysis, FIGO stage, DEF6 and p16 were associated with poor prognosis. DEF6 expression was the only independent prognostic factor correlated with shorted OS (HR 2.115; P = 0.025) and DFS (HR 2.248; P = 0.016) upon multivariate analysis. CONCLUSIONS: DEF6 expression may serve as an independent prognostic factor, and interacted positively with p16 toward high tumor stage and shorter survival.

Noninvasive and invasive micropapillary (low-grade) serous carcinoma of the ovary: a clinicopathologic analysis of 135 cases.

Reports describing the behavior of micropapillary serous carcinomas (MPSCs) of the ovary have focused on those that are noninvasive. There are only very limited data on the behavior of those that are invasive. To further characterize the behavior of MPSCs, invasive versus noninvasive primary tumors were distinguished based on the presence or absence of destructive infiltrative growth. To qualify for inclusion, invasive MPSCs, like the noninvasive tumors, were required to display a micropapillary architecture and low-grade nuclei. A total of 135 cases of MPSC were identified: 96 noninvasive and 39 invasive. On follow-up, survival for 10 patients with stage I noninvasive and invasive MPSCs was 100%, and survival for women with stage II and III noninvasive and invasive MPSCs with noninvasive implants was 80%. In contrast, the 5-year and 10-year survival for patients with stage II and III noninvasive MPSCs with invasive implants was 85% and 55%, respectively. The 5-year and 10-year survival for women with invasive MPSCs and invasive implants was 55% and 45%, respectively. The median time from diagnosis to death for women with noninvasive and invasive MPSCs with invasive implants was 60 months (range 33-240 months). The indolent behavior of these low-grade carcinomas distinguishes them from conventional serous carcinomas, which are high-grade aggressive neoplasms. Five of six patients with small (<5 mm) MPSCs in whom follow-up was available presented with high stage disease. Of these five women, three are alive and well and two are alive with disease (one with invasive and one with noninvasive implants). Nearly three fourths of noninvasive MPSCs were associated with atypical proliferative serous tumors, adenofibromas, or both, and 62% of invasive MPSCs were associated with noninvasive MPSCs, atypical proliferative serous tumors, and adenofibromas, alone or in combination. In addition to the frequent mixtures of these tumor components, transitions between them were common. These data in conjunction with recent molecular genetic studies strongly suggest that MPSCs (low-grade carcinomas) arise from atypical proliferative serous tumors unlike conventional serous carcinomas (high-grade carcinomas), which appear to develop de novo. The findings provide further support for the hypothesis that there are distinct pathways of carcinogenesis for low-grade and high-grade serous carcinoma of the ovary.

Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators.

BACKGROUND: The behavior of ovarian serous borderline tumors (SBTs) and significance of various prognostic factors are unclear and difficult to evaluate because of inconsistencies and confusion in the literature. Recent studies have suggested that the morphological features of the primary tumor (presence or absence of micropapillary features) and the peritoneal "implants" (presence or absence of invasive features) can reliably subclassify SBTs into benign and malignant types. The aim of the current review was to test two hypotheses. First, that the alleged malignant behavior of SBTs is poorly documented, and second, that the morphological features of the primary ovarian tumors and the associated peritoneal implants are sufficient to separate SBTs into benign and malignant types, thereby obviating the need for the category. METHODS: 245 studies reporting approximately 18,000 patients with borderline ovarian tumors were reviewed. After excluding series that lacked clinical follow-up or were not analyzable for other reasons, there remained 97 reports that included 4,129 patients. In addition to recurrences and survival, we evaluated the type of peritoneal implants, microinvasion, lymph node involvement, late recurrences, and progression to carcinoma, as these features have served as the underpinning of the concept of "borderline malignancy" or "low malignant potential." RESULTS: Among 4,129 patients with SBTs reviewed, the recurrence rate after a mean follow-up of 6.7 years was 0.27% per year for stage I tumors, the disease-free survival was 98.2%, and the overall disease-specific survival rate was 99.5%. For patients with advanced-stage tumors, the recurrence rate was 2.4% per year. However, the majority (69%) of reported recurrences were not pathologically documented, and only 26 cases (8.4% of all recurrences) were documented to have recurred from an adequately sampled ovarian tumor. The most reliable prognostic indicator for advanced stage tumors was the type of peritoneal implant. After 7.4 years of follow-up, the survival of patients with noninvasive peritoneal inplants was 95.3%, as compared with 66% for invasive implants (P < .0001). Microinvasion in the primary ovarian tumor was associated with a 100% survival rate at 6.7 years, and lymph node involvement was associated with a 98% survival rate at 6.5 years. The few reported cases of stage IV disease, progression to invasive carcinoma, and very late (>20 years) recurrences were poorly documented. The survival for all stages among approximately 373 patients in 6 prospective randomized trials followed for a mean of 6.7 years was 100%. CONCLUSION: Surgical pathological stage and subclassification of extraovarian disease into invasive and noninvasive implants are the most important prognostic indicators for SBTs. Survival for stage I tumors is virtually 100%. Survival for advanced stage tumors with noninvasive implants is 95.3%, whereas survival for tumors with invasive implants is 66%. Invasive implants behave as carcinomas and are most likely metastatic. The precise nature of so-called noninvasive implants is not clear, but they behave in a benign fashion. The presence of a micropapillary architecture in the primary ovarian tumor is a strong predictor of invasive implants. These data support the recommendation that ovarian tumors with a micropapillary architecture be designated "micropapillary serous carcinomas," and those lacking these features, "atypical proliferative serous tumors."

Multivariate analyses of DNA index, p62c-myc, and clinicopathological status of patients with ovarian cancer.

AIM: To determine if either DNA index or p62c-myc is an independent prognostic variable in ovarian cancer. METHODS: Multivariate and univariate analyses of the relation between DNA index, p62c-myc, FIGO stage, histological type, tumour grade, completeness of surgery, and patient survival in ovarian cancer were examined. RESULTS: Multivariate analysis showed significant association of survival only with stage and grade. There was no relation between survival and DNA index. CONCLUSIONS: DNA index is not an independent prognostic variable in ovarian cancer.

Cystic neoplasms of the pancreas. A clinicopathologic study, including DNA flow cytometry.

OBJECTIVE: To review the classification, clinical behavior, and appropriate therapy for cystic neoplasms of the pancreas. We examined patient demographics, clinical parameters, preoperative imaging modalities, histologic findings, and tumor DNA content to determine which best predict outcome. DESIGN: Case series and survey of pathologic specimens. SETTING: Tertiary care center. PATIENTS: Twenty-two patients with cystic neoplasms of the pancreas treated at affiliates of Northwestern University Medical School, Chicago, Ill. MAIN OUTCOME MEASURES: Predictive value of preoperative testing, tumor DNA content, patient survival. RESULTS: In 20 patients undergoing computed tomographic scan, the tumor was visualized in every case. All other imaging studies evaluated were less likely to demonstrate the lesion. Eight of 10 patients with serous cystadenomas were alive with no evidence of disease at the time of this report; one patient was alive with local recurrence, and a second patient had died of unrelated causes. All patients with mucinous cystadenomas were alive with no evidence of disease. Three of seven patients with cystadenocarcinomas had aneuploid, high S-phase tumors, and one had a diploid, high S-phase tumor; all four died (mean survival, 4.8 months). Two patients with cystadenocarcinomas had diploid, low S-phase tumors; both were long-term survivors but died of their disease at 8.6 and 9.3 years. CONCLUSIONS: (1) Computed tomographic scan is the most valuable diagnostic imaging study for preoperative evaluation of these patients. (2) Precise preoperative determination of tumor type is not possible. (3) DNA flow cytometry may help identify patients with aggressive tumors who may benefit from adjuvant chemoradiation.