Immunohistochemical c-kit expression in uterine serous carcinoma tissue.

AIM: Uterine serous carcinoma (USC) is an aggressive tumor that represents only 10% of endometrial cancer cases but accounts for a disproportionate number of deaths due to uterine cancer. Advances in the development of specific c-kit receptor-targeted drugs have promoted its potential therapeutic application as a target in tumor-related diseases. The aim of the present study was to evaluate imunohistochemical expression of c-kit in USC tissue in order to assess whether positive cases can be candidates for targeted therapy. MATERIALS AND METHODS: C-kit expression assessment by immunohistochemistry was performed on deparaffinized sections of paraffin-embedded tissue blocks of confirmed consecutive available USC uterine specimens of patients diagnosed from 2000 to 2014. Sections of gastrointestinal stromal tumor (GIST) tissue known to contain c-kit served as positive controls. RESULTS: Immunohisto- chemical c-kit staining was not observed in any of 31 USC tissue samples examined. Intense staining was observed in the sections of GIST tissue. CONCLUSION: The present results may indicate that primary USC is not a candidate for c-kit targeted therapy.

Patient-tailored conservative surgical treatment of invasive uterine cervical squamous cell carcinoma. A review.

The aim of this paper was to review currently available data regarding the results of a more conservative, patient-tailored surgical approach in selected cases of early invasive uterine squamous cell carcinoma (SCC). A PubMed search of investigations in the English language published from January 2000 to September 2012 containing the terms conservative surgery, conservative treatment, trachelectomy, parametrectomy, lymphadenectomy, sentinel lymph node biopsy and fertility sparing surgery in combination with SCC was made. Conization only is optimal for women with stage Ia1 disease mainly in tumors without lymph vascular space involvement (LVSI). In stage Ib1 patients interested to maintain reproductive capacity, vaginal or abdominal radical trachelectomy are the procedures of choice. Patients with small tumors (<2 cm), no deep invasion, no LVSI, and negative pelvic nodes are at very low risk of parametrial involvement and parametrectomy may be omitted in them. Such patients may benefit from less radical surgery and may be candidates for simple hysterectomy, simple trachelectomy, or conization with pelvic lymphadenectomy. Sentinel lymph node (SLN) biopsy is apparently a good predictor of node metastases and allows the performance of lymphadenectomy only in SLN positive cases. Thus lymphadenectomy may also be omitted in some patients. In young women with locally advanced tumors, neoadjuvant chemotherapy followed by fertility-sparing surgery may also be a feasible treatment. A more conservative, patient-tailored surgical approach in selected cases of early SCC is possible resulting in lower morbidity and preservation of fertility without compromising the outcome.

The effect of coexisting uterine myomas on clinico-pathological variables of endometrial carcinoma.

PURPOSE: To assess the prevalence of leiomyomas in patients with endometrial carcinoma (EC) and the association of their presence with clinico-pathological variables and with survival. MATERIALS AND METHODS: A retrospective chart review was conducted of all endometrial carcinoma (EC) patients diagnosed and treated in the present institution between 2002 and 2008. Selected clinical data were abstracted from medical records. Pathological data such as the presence of myomas (any size), tumor grade, depth of myometrial invasion presence of lymphovascular space involvement (LVSI), and the presence of metastases, are based on the original pathology report. RESULTS: Coexisting myomas were found in 74 (56.9%) of 130 EC patients diagnosed during the study period. No significant difference with regard to age, histological type, stage, grade, depth of myometrial invasion, LVSI, lymph node involvement, and presence of metastases (other than lymph node involvement) was found between patients without and with myomas. There was also no significant difference in survival of EC patients without and with coexistent myomas. CONCLUSION: The present data seem to indicate that the presence of myomas does not affect clinico-pathological variables of EC patients nor their survival.

Cox-2 immunohistochemical expression in epithelial ovarian carcinoma and platin sensitivity.

PURPOSE: The aim of the study was to assess whether COX-2 expression in epithelial ovarian carcinoma (EOC) tissue can distinguish between platin-sensitive and platin-resistant tumors. METHODS: Clinical and histological data were obtained from medical records of EOC patients diagnosed between the years 1995 and 2005. Patients in complete clinical remission for > 6 months after discontinuation of first-line chemotherapy were considered to be platin-sensitive. Survival of < or = 2 and > 5 years after diagnosis was considered as short- and long-term survival, respectively. Immunohistochemistry staining was performed on deparaffinized sections of tissue blocks obtained at first surgery. The intensity of staining and the percentage of stained cells was assessed by two pathologists blinded to clinical data and a scoring index was calculated. RESULTS: Among 79 patients a positive stain (> 10% of cells stained) was observed in 61 (77.2%). No statistically significant association between distribution of platin sensitivity and immunohistochemical COX-2 staining parameters was observed, although the rate of long-term survival was significantly higher among platin-sensitive then among platin-resistant/unresponsive patients. CONCLUSIONS: Immunohistochemically determined COX-2 expression in EOC is not associated with platin sensitivity and survival.

Ovarian carcinoma apparently confined to the ovaries--the accuracy of surgical staging in Israel.

BACKGROUND: In order to allot an ovarian malignancy to FIGO Stage I, in addition to abdominal exploration and the basic operation, it is also necessary to do peritoneal washings for cytological examination, random peritoneal biopsies (including diaphragmatic assessment) and omental and retroperitoneal lymph node assessment. OBJECTIVE: The aim of the study was to assess the accuracy of surgical staging of ovarian carcinoma classified as Stage I in Israel. METHODS: Included were all patients with histologically confirmed epithelial ovarian carcinoma (EOC) classified as Stage I in a data base of a nationwide incidence case control epidemiological study of ovarian carcinoma conducted in Israeli Jewish women during the period 1994-1999. Surgical staging data of these patients were retrieved from pathological reports, and from clinical records when available. RESULTS: A total of 182 EOC patients were classified as Stage I. About 86% of the patients underwent hysterectomy and bilateral salpingo-oophorectomy. The most commonly performed staging procedure was omental assessment (85.2%) while peritoneal biopsy was the least common one (34.1%). In 17 (9.3%) of the patients none of the staging procedures were done and only 34 (18.7%) had optimal staging. CONCLUSION: Although the data are from a decade ago, they seem to indicate the need for an increased awareness of the necessity for accurate surgical staging of tumors apparently confined to the ovaries since it can identify a group of patients who require surgical therapy alone and who can be spared the complications, inconvenience and cost of adjuvant chemotherapy.

Platin sensitivity and long-term survival in Stage III epithelial ovarian cancer patients.

PURPOSE: The aim of the present study was to assess the effect of platin sensitivity on long-term survival of Stage III epithelial ovarian cancer (EOC) patients. METHODS: The records of all histologically confirmed Stage III EOC and PPC patients diagnosed during 1995-2006 were reviewed. A comparison of selected characteristics was made between long-term (> 5 years) and short-term (< 3 years) survivors. RESULTS: Among 58 Stage III patients, 20 had long-term and 18 short-term survival. The rate of platin sensitive patients in long-term survivors was significantly higher than in short-term survivors (95.0% vs 27.8%, p < 0.001). The sensitivity and specificity of platin sensitivity for long-term survival was 95% and 72.2%, respectively, and the positive and negative predictive value was 79.2% and 92.8%, respectively. No statistically significant difference between the groups was found with regard to other selected characteristics. CONCLUSION: The rate of platin sensitive patients was significantly higher among long-term survivors than among short-term survivors but the specificity and positive predictive value of platin sensitivity for long-term survival prediction were relatively low precluding its practical clinical use.

A decreasing incidence of ovarian carcinoma in Israel.

The aim of the present study was to assess the incidence trend of invasive epithelial ovarian carcinoma in Israel. We assessed the incidence rate of invasive epithelial ovarian cancer in Israeli Jewish women during the 10-year period from 1993 to 2002 based on data obtained from the population-based Israel National Cancer Registry. There was a gradual significant decrease in the incidence of ovarian cancer from 9.64 in 1993 to 6.55 in 2002. The decrease in incidence was evident in all ethnic groups except those born in Asia and in all the age groups older than 35 years. The decrease in incidence of ovarian carcinoma is gratifying, but its reason remains obscure.

Management of endometrial carcinoma with cervical involvement. An unsettled issue.

The purpose of the present report is to review the various management options of endometrial carcinoma with cervical involvement. A Medline literature search for publications dealing with endometrial carcinoma (EC) with cervical involvement and treatment was made. Although many publications deal with EC with cervical involvement there is a lack of prospective controlled trials. Only one prospective randomized phase III trial has been published. The inaccuracies of clinical staging, the scarcity of reports with surgically staged patients, the multiple types of cervical involvement and prognostic indicators and the remarkable variations in treatment render it difficult to compare outcome results between publications. The small number of patients in many of these studies and their retrospective uncontrolled nature add to this difficulty. There are conflicting reports with regard to factors affecting outcome, also complicating the management issue of endometrial carcinoma with cervical involvement and comparison of treatment results. The optimal management of EC with cervical involvement remains to be established.

Whole-abdomen, single-dose consolidation radiotherapy in patients with pathologically confirmed complete remission of advanced ovarian epithelial carcinoma: a long-term survival analysis.

The value of consolidation therapy in advanced epithelial ovarian carcinoma patients is controversial. The aim of the present study was to assess the long-term survival of patients with a pathologically confirmed complete remission who had consolidation by single-dose, whole-abdominopelvic radiotherapy. Of 96 histologically confirmed stage II-IV epithelial ovarian carcinoma patients who underwent cytoreductive surgery followed by high-dose, platin-based chemotherapy, 57 were in complete clinical remission at the end of therapy and 50 underwent a second-look laparotomy. The study group comprises 32 consecutive patients who had no pathological evidence of disease and who received 800 cGy single-dose, whole-abdominal radiotherapy by an 8 MEV linear accelerator in a single fraction. The absolute 5-year survival and the actuarial 10-year survival were 78.7 and 63.3%, respectively. The survival was significantly better in patients who had < or =2 cm residual disease at the completion of the original operation. No severe postradiation complications were encountered. Mild complications were seen in three (9.4%) patients. Our data indicate a favorable long-term survival of patients with a negative second-look laparotomy who had consolidation with single-dose, whole-abdominal radiotherapy. These results seem to suggest that a collaborative, prospective, randomized multiarm study is indicated to solve the controversial issue of consolidation therapy.

Expression of p27 and p53: comparative analysis of uterine carcinosarcoma and endometrial carcinoma.

The aim of the study was to assess both p27 and p53 expression in the stromal and epithelial component of carcinosarcoma and to assess if their expression in the latter is different than in endometrial carcinoma. Immunohistochemical staining for p27 and p53 was performed on paraffin-embedded tissue blocks of 18 uterine specimens with carcinosarcoma and their expression assessed. Their expression in the epithelial element was also compared to that in 35 paraffin-embedded tissue blocks of endometrial endometrioid carcinoma. Reduced p27 expression was observed in a similarly high proportion of the stromal (77.8%) as well as of the epithelial component (66.7%) of carcinosarcoma. Although statistically not significant, the proportion of reduced p27 expression in endometrial carcinoma (85.7%) was higher than in the epithelial element of carcinosarcoma. The percentage of p53 overexpression in both elements of carcinosarcomas and in endometrial carcinomas was low and also similar (27.8 and 20.0%, respectively). Our results indicate that reduced p27 expression is common and p53 overexpression is infrequent in carcinosarcoma. Their similar rates of expression in the stromal and epithelial elements of the tumor support the contention of a monoclonal origin of carcinosarcoma. Unexpectedly, reduced p27 expression is more common in endometrial carcinoma than in the epithelial element of carcinosarcoma, in spite of the less favorable prognosticators and outcome in the latter. Further studies of p27 expression in carcinosarcoma are indicated to establish its clinical value in this aggressive malignancy.

Premalignant lesions of the uterine cervix in a large cohort of Israeli Jewish women.

Israeli Jewish women are at low risk for cancer of the uterine cervix. In view of absent screening programs in Israel, there are only scarce data available with regard to results of PAP smears. The aim of this study was to assess the incidence of premalignant cervical lesions in the largest sample of PAP smears reported so far from Israel. We retrospectively analyzed the results of 297,849 PAP smears, which had been examined in a single laboratory, during 9 years (1991-1999). The incidence of low- and high-grade squamous intraepithelial was 0.69% and 0.29%, respectively. Our data indicate similar incidence rates for premalignant lesions in Jewish Israeli women as observed in Western countries, but no increase during the study period. In spite of relatively high incidence rates for premalignant lesions of the uterine cervix, the incidence rate for invasive cervical cancer remains conspicuously low. For unknown reason the conversion rate from premalignant cervical lesions to invasive cancer is lower in Israeli Jewish women than in European and North American women. We discuss possible reasons for this phenomenon and suggest that at this time mass screening for cervical cancer in Israel may probably not be justified.

Reflections on the FIGO surgical staging of invasive epithelial ovarian cancer.

The main aims and requirements of any staging system are: to determine the anatomical extent of disease, to allow uniform reporting of treatment results, comparison of their efficacy and pooling of data from various institutions. It should be based on the mode of spread of the neoplasm, take into consideration prognostic risk factors and be of prognostic value. A critical review of the FIGO staging system for ovarian carcinoma indicates that these aims and requirements are not entirely fulfilled. Following are some examples. It does not include exact recommendations for comprehensive surgical staging in apparently early ovarian cancer and staging is therefore not performed uniformly. The presence of parenchymal liver and lung metastasis may be facilitated by modern imaging devices. However, according to FIGO rules only simple X-ray procedures are allowed preoperatively. The correlation between increasing stage and survival is inconsistent and sometimes contrary to that expected. Many known prognostic factors are not included in the present staging system. Although the aims of data pooling and of uniform reporting of treatment results have been achieved, the validity of some comparisons are questionable in view of the variations in staging. The intent of this review was not to belittle the major contribution of staging to research, understanding and management of ovarian carcinoma, but to highlight its deficiencies. New data have accumulated since the FIGO staging system of ovarian carcinoma has been adopted and should prompt consideration of modifications such as incorporation of modern diagnostic procedures and of some established prognostic markers and reshuffling of certain substages.

Frequency of BRCA mutations in primary peritoneal carcinoma in Israeli Jewish women.

OBJECTIVE: The aim of the present study was to compare demographic and clinical characteristics of primary peritoneal carcinoma (PPC) to ovarian carcinoma (OvC) with regard to BRCA mutation frequencies. METHODS: Incident cases of histologically confirmed cancer of the ovary or peritoneum diagnosed in Israeli Jewish women between March 1, 1994, and June 30, 1999, were identified within the framework of an ongoing nationwide epidemiological study of these neoplasms in Israel. The present study comprises 609 (81.5% of 747) Jewish women with epithelial stage III-IV OvC and 68 (77.3% of 88) Jewish women with PPC who were genetically tested for the BRCA mutations. Data from each patient were collected by the aid of a prestructured questionnaire and medical records. Blood samples or tumor tissue was tested for the 185delAG and 5382insC mutations in BRCA1 and the 6174delT mutations in BRCA2. RESULTS: A carrier rate of 28% of any BRCA 1/2 mutation was observed among the PPC group and of 30% among the invasive stage III-IV OvC. No differences were found between PPC and OvC neither in the overall distribution of BRCA1/2 mutation carrier rates nor according to type of mutation, age, ethnic origin, and histologic subtype. Among women with a positive family history, a higher rate of mutation carriers was observed in the PPC group compared to the OvC group (72.7 vs 43.8%, respectively, P = 0.07). CONCLUSIONS: The similar frequency distribution of BRCA1/2 mutations in PPC and OvC observed in the present study indicates that these mutations may predispose to PPC as well and that this neoplasm is part of the hereditary breast-ovarian cancer syndrome.

Codon 72 polymorphism of p53 in Israeli Jewish cervical cancer patients and healthy women.

Recently it has been found that the presence of homozygous arginine polymorphism at codon 72 of p53, represents a significant risk factor in the development of HPV-associated cervical cancer. The incidence of cervical carcinoma is persistently very low in Israeli Jewish women for unknown reasons. The incidence among those of North African origin is relatively higher. The aim of the present study was to assess the frequency distribution of the p53 homozygous arginine polymorphism in cervical cancer patients and in a population sample of healthy Israeli Jewish women in order to determine whether the incidence pattern among them is genetically based. The cases consisted of 23 Israeli Jewish patients with histologically confirmed squamous cell carcinoma of the cervix. A group of 162 randomly chosen Israeli Jewish healthy participants, considered to represent the general population, comprised the controls. The germline p53 polymorphism at codon 72 was determined by PCR in DNA obtained from a blood sample taken from each subject. Homozygous arginine was found in 34.8% of cases and in only 14.8% of controls. This difference was statistically significant (P = 0.01). The frequency of homozygous arginine polymorphism in controls was lower than in any other population hitherto reported. It was significantly more common among those of North African than among those of other origin (30.3% vs. 10.8%; P < 0.01). It may be assumed that the low incidence of cervical cancer in Israeli Jewish women and the differences between the ethnic groups may be related to the frequency pattern of the homozygous arginine p53 polymorphism

Tissue and serum CA125 expression in endometrial cancer.

Serum CA125 is elevated in some endometrial cancer patients. The purpose of the present study was to assess the correlation between the presence of CA125 in endometrial cancer tissue and elevated CA125 serum levels. Serum levels of CA125 were examined in 39 patients with endometrial cancer prior to definitive surgery. After diagnosis reconfirmation, additional slides were prepared from each case for immunohistochemical staining for anti-CA125 antigens. Of the 39 patients, 28 had endometrioid endometrial carcinoma (EEC) and 11 had mixed mesodermal sarcoma (MMS). In EEC, 21.4% of the patients had an elevated CA125 serum level, and that correlated with stage (P = 0.02) but not with grade. The percentage of EEC patients with positive tissue staining was significantly higher than the percentage with elevated serum levels (89.3% vs. 21.4%, P < 0.0001). No correlation between positive tissue staining and stage or grade was observed. In MMS the percentage of positive tissue staining was also higher than that with elevated serum CA125 levels and the percentage with elevated serum levels was higher than in EEC. However, the differences were statistically not significant. Our study indicates that the majority of EEC tissues contain CA125 and that the percentage of positive CA125 tissue staining is significantly higher than that of elevated CA125 serum levels. This indicates the presence of some mechanism that prevents the access of CA125 into the circulation. This mechanism is probably less effective in more advanced EEC's and in MMS.

Conversion of laparoscopy to laparotomy due to adnexal malignancy.

PURPOSE: The purpose of the present report was to assess the conversion rate from laparoscopy to laparotomy due to adnexal malignancy and to identify factors that might assist in the selection of the appropriate operative approach in patients with suspicious adnexal masses. METHODS: A retrospective review of the medical records of women who underwent laparoscopy due to ultrasonically complex adnexal masses. Ninety-five consecutive patients fulfilling these criteria, were identified. A comparison of patients with benign tumors who had laparoscopy only to those with invasive malignancies in whom laparoscopy was converted to laparotomy was performed. RESULTS: Malignancy was diagnosed in 18 (18.9%) patients. In 13 patients with malignancy (two borderline and 11 invasive), comprising 72.2% of the malignancies and 13.7% of the total group with complex adnexal masses, the laparoscopy was converted to laparotomy. Age of more than 50 years and a serum CA125 level above 35 U/ml were significantly more common in the malignant than in the benign group (90.9% vs. 15.6% and 63.6% vs. 11.6%, respectively; p < 0.0001 and p < 0.003, respectively). When both factors were present, the sensitivity and specificity for malignancy were 73.3% and 93.2%, respectively, and the positive and negative predictive values 73.3% and 95.6%, respectively. CONCLUSION: When an ultrasonically complex adnexal mass is encountered, predictive factors for malignancy should be taken into account before the mode of intervention is chosen. The conversion from laparoscopy to laparotomy because of an invasive malignant tumor is acceptable, if it is performed immediately and a gynecologic oncologist is on stand-by.

Effect of BRCA mutations on the length of survival in epithelial ovarian tumors.

PURPOSE: To study the role of BRCA mutations in ovarian cancer survival. PATIENTS AND METHODS: Blood samples and specimens of ovarian tumors (whenever blood samples were not available) at the time of the primary surgery were obtained in the course of a nationwide case-control study of women with ovarian cancer in Israel. The three common BRCA mutations in Israel (185delAG, 5382insC, and 6174delT) were analyzed with a multiplex polymerase chain reaction to amplify the exons containing the three mutations using fluor-labeled primers in a single reaction. Because each mutation is a small insertion or deletion, they can be detected as length polymorphisms. Patients were followed for up to 5 years (range, 20 to 64 months). Statistical analysis was performed using the Kaplan-Meier method and the log-rank test. Stepwise Cox regression analysis was used for determination of independent prognostic factors. RESULTS: This report is based on 896 blood or tumor specimens analyzed for the presence of the BRCA mutations. Of these, 234 women (26.1%) were found to be positive. A significant difference in survival pattern was found between BRCA1/BRCA2 carriers and noncarriers among the women with invasive ovarian cancer (median survival, 53.4 months v. 37.8 months; 3-year survival, 65.8% v. 51.9%, respectively). These differences were independent of age at diagnosis or stage of the disease. CONCLUSION: Our data indicate that the survival of patients with ovarian cancer is affected by BRCA germline mutation, at least in the early years after diagnosis.

p53 expression in tissue adjacent to endometrial carcinoma.

OBJECTIVE: Since several investigations did not demonstrate the presence of altered p53 in endometrial hyperplasias, it has been concluded that these alterations constitute a relatively late event in endometrial carcinoma. The aim of the present study was to assess the presence of p53 in the tissue adjacent to endometrial carcinoma in attempt to elucidate the relationship between these tissues. METHODS: New slides were prepared from paraffin-embeded tissue blocks of 49 endometrial endometrioid carcinoma hysterectomy specimens so that in each case tumor tissue and adjacent uninvolved endometrium were represented. Immunohistochemical staining for p53 detection was then performed. RESULTS: In 43 of the 49 hysterectomy specimens evaluated, the tissue adjacent to the endometrial carcinoma was non hyperplastic and in six it was hyperplastic. Positive immunohistochemical staining was found in 22 (44.9%) of endometrial carcinomas and in eight (16.3%) of the adjacent tissues. A statistically significant higher percentage of hyperplastic adjacent tissues than non-hyperplastic adjacent tissues were immunohistochemically p53 positive (50.0% vs 11.3%; p = 0.047). CONCLUSIONS: Our findings may indicate that p53 alterations are not necessarily a late event in endometrial endometrioid carcinogenesis. Since a large proportion of tissues adjacent to endometrial carcinoma do not show p53 alterations, other early cellular events may also play a role.

Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation.

BACKGROUND: Multiparity and the use of oral contraceptives reduce the risk of ovarian cancer, but their effects on this risk in women with a BRCA1 or BRCA2 mutation are unclear. METHODS: We conducted a population-based case-control study of ovarian cancer among Jewish women in Israel. Women were tested for the two founder mutations in BRCA1 and the one founder mutation in BRCA2 that are known to be common among Jews. We estimated the effects of parity and oral-contraceptive use on the risk of ovarian cancer in carriers and noncarriers in separate analyses that included all control women, who did not have ovarian cancer. RESULTS: Of 751 controls who underwent mutation analysis, 13 (1.7 percent) had a BRCA1 or BRCA2 mutation, whereas 244 of 840 women with ovarian cancer (29.0 percent) had a BRCA1 or BRCA2 mutation. Overall, each additional birth and each additional year of use of oral contraceptives were found to lower the risk of ovarian cancer, as expected. Additional births were protective in separate analyses of carriers and noncarriers, but oral-contraceptive use appeared to reduce the risk only in noncarriers; among carriers, the reduction in the odds of ovarian cancer was 12 percent per birth (95 percent confidence interval, 2.3 to 21 percent) and 0.2 percent per year of oral-contraceptive use (-4.9 to 5.0 percent). CONCLUSIONS: The risk of ovarian cancer among carriers of a BRCA1 or BRCA2 mutation decreases with each birth but not with increased duration of use of oral contraceptives. These data suggest that it is premature to use oral contraceptives for the chemoprevention of ovarian cancer in carriers of such mutations.