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.

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.

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.

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.

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.

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.

Antibodies to Herpes simplex virus in Jewish women with cervical cancer and in healthy Jewish women of Israel.

Herpes simplex virus (HSV) antibody titers were examined in sera from 39 Jewish women with squamous cell carcinoma of the uterine cervix (CaCx) and in sera from controls matched by age and country of origin. Highly significant differences were found between the cases and controls for both HSV type 1 (HSV-1) and HSV type 2 (HSV-2). Compared to findings in other demographic areas, the geometric mean titer (GMT) of HSV-1 among the CaCx cases were considerably higher, whereas the GMT for HSV-2 was in the same range. The percentage of HSV-2-positive patients, as defined by the HSV-2/HSV-1 antibody titer ratio was low compared to that found in other demographic areas; this was presumably due to the high incidence of HSV-1 infection in the population. The HSV-1 and HSV-2 infection rate in the Israeli Jewish female population was estimated by antibody titers for 94 healthy subjects. The GMT of HSV-1 was considerably higher, whereas the GMT of HSV-2 was lower, than those reported elsewhere. The association found previously between HSV-2 and CaCx remained true for Jewish women. Their low incidence of CaCx, which did not seem to result from lower susceptibility, might be explained by the low incidence of HSV-2 infection.

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.

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.

Insulin-like growth factor-I (IGF-I) and IGF-binding protein-2 are increased in cyst fluids of epithelial ovarian cancer.

Expression of insulin-like growth factor-I (IGF-I), its receptor, and IGF-binding proteins (IGFBPs) by epithelial ovarian cancer cells and its mitogenic effect on these cells in vitro suggest that IGF-I may have a role in the regulation of human ovarian cancer. To examine this role in vivo, we explored the IGF-I/IGFBP system in sera and cyst fluids of women undergoing surgery for simple and other benign cysts (n = 20) and borderline (n = 5) and invasive malignant epithelial neoplasms (n = 11). The IGF-I level was significantly higher in cyst fluid from invasive malignant compared to cyst fluid in benign neoplasms (16.1 +/- 2.2 vs. 7.3 +/- 1.2 nmol/L; P = 0.002). Although benign cysts contained almost no IGFBP, high IGFBP-2 levels were detected in malignant cysts regardless of histological type. Serum IGFBP-2 levels were also higher in women with invasive malignancy than in benign controls (1.32 +/- 0.32 vs. 0.53 +/- 0.07 relative units; P = 0.004). IGFBP-2 was higher in cyst fluids than in the corresponding sera, implying local production of this protein. Estradiol was high in fluid from invasive malignant cysts of postmenopausal women and correlated with IGF-I in the cyst fluid. Levels of IGF-I, IGFBP-2, and estradiol in cyst fluid could discriminate between benign and malignant neoplasms, except for the endometrioid-type tumors (n = 2). Our data support a role for IGF-I in the proliferation of ovarian cancer and suggest that IGF-I and estradiol interact in regulating this malignancy.

Unoccupied nuclear receptors for estrogen in human endometrial tissue.

PIP: The nuclear content of estrogen-binding sites in normal and pathological endometrial tissue was studied. Extracts of cell nuclei from normal, nonmalignant, and cancerous human endometrial tissues were used, and at 0 degrees centigrade were found to contain material capable of binding estradiol in vitro. Only binding sites unoccupied by endogenous estrogen were determined. Estrogenic receptor (ER) character of this binding was demonstrated by 3 findings: 1) high affinity of binding to estradiol; 2) specificity of binding, competition by diethylstilbestrol and estriol for estradiol binding, and absence of competition by cortisol, progesterone, and 5 alpha-dihydrotestosterone; and 3) sedimentation constant at about 4S in sucrose density gradient. Next, occupied receptors were determined at 30 degrees centigrade. Both occupied and unoccupied receptors were measured by a single saturating dose of 7.5 nM tritiated estradiol with or without a 100-fold excess of diethylstilbestrol to estimate the amount of nonspecific binding. All specimens assayed had unoccupied nuclear receptors. This unoccupied receptor comprised from 9-37% of the total estradiol receptors (cytoplasmic plus nuclear). Such a large percentage of unoccupied nuclear receptors in both normal and pathological endometrial material may indicate that the unoccupied receptor is a necessary product in the normal mechanism of estradiol action.^ieng

High levels of protein carboxyl methyltransferase in well-differentiated human endometrial carcinoma.

The levels of protein carboxyl methyltransferase, an enzyme that methylates free carboxyl groups of proteins, were determined in normal human proliferative and secretory endometrium and in poorly and well-differentiated endometrial carcinoma. Protein carboxyl methyltransferase activity was 67% higher in the well-differentiated carcinoma than in the normal tissues, while similar enzyme levels were observed in the two normal tissues and in the poorly differentiated carcinoma. The results suggest that in the well-differentiated tumor there is excessive protein methylation and offer a possible biochemical probe for distinguishing between the two types of tumor.

Expression of heparanase, Mdm2, and erbB2 in ovarian cancer.

Ovarian cancer is the most lethal of gynecological malignancies. Yet early diagnosis and prognosis are far from being satisfactory. Degradation of heparan sulfate proteoglycans by heparanase appears to play an important role in the invasiveness of tumor cells through the basement membrane and into the extracellular matrix. Recent cloning of the heparanase gene and generation of monoclonal antibodies against the enzyme permit to examine tumor cell expression of the enzyme. The aim of the present study was to assess heparanase activity and localization in various subtypes of epithelial ovarian cancer in correlation with oncogene expression. Histologically confirmed malignant ovarian tissue from ten women and tissue from 2 benign ovarian tumors and 4 normal ovaries were assessed for heparanase presence, activity and localization, incidence of apoptosis and expression of the oncogenes erbB2 and Mdm2. Heparanase immunohistostaining and activity were present in mucinous carcinomas and were more intense than in endometrioid and in serous carcinomas. The lowest activity was observed in benign ovarian tumors and normal ovaries. In ovarian carcinomas the enzyme was intensely concentrated in the cytoplasm of the cancerous cells. In contrast, in normal ovaries and benign tumors the enzyme was predominantly localized in endothelial cells lining blood capillaries. The rate of apoptosis was considerably higher in mucinous and endometrioid carcinomas, and was lower in serous and primary peritoneal carcinomas. Extremely high concentration of heparanase was often demonstrated in apoptotic cells. Endometrioid and serous carcinomas showed high expression of Mdm2 and erbB2 while mucinous carcinomas showed low expression. In benign ovarian tumors and normal ovaries the expression of both oncoproteins was extremely low. In conclusion ovarian carcinomas demonstrate higher levels of heparanase than benign tumors and normal ovaries suggesting that the enzyme may play an important role in metastatic spread of the cancerous cells. Apoptosis may be a significant part of the mechanism of the enzyme release into the extracellular space. Although heparanase activity seems to play an essential role in tumor progression, expression of oncogenes, such as erbB2 and Mdm2 seems to play the dominant role in the development of ovarian cancer.

Familial ovarian cancer in Israeli Jewish women.

Among 310 women with ovarian cancer of epithelial origin, eight ovarian cancer-prone families were identified, accounting for 24 cases. Five first-degree relatives underwent prophylactic oophorectomy, and early ovarian carcinoma was diagnosed in one of them. Familial aggregation of ovarian cancer occurs in the Israeli Jewish population.

Prospective follow-up of patients with hydatidiform mole.

Of 74 Jewish patients with histologically confirmed hydatidiform mole (HM), 37 (50%) were referred to the hospital after the 15th week of pregnancy. In only 5.4% was HM the referral diagnosis. A correct diagnosis prior to uterine evacuation was made in only 29 (39.2%), and this was mainly when the uterus was normal or larger than expected for gestational age. The percentage with urinary human chorionic gonadotropin hemagglutination inhibition titers below 100,000 U/liter was significantly smaller in those with a smaller uterus as compared with those with a uterus of normal size or larger than expected. The incidence of persistent trophoblastic disease (PTD) following HM without the use of prophylactic chemotherapy was 12.2%. Patients with a large-for-date uterus had a greater potential for this outcome. All patients with PTD responded well to treatment, which consisted mainly of chemotherapy, and remained free of disease after therapy was completed.

Immediate and late outcome of vaginal myomectomy for prolapsed pedunculated submucous myoma.

During a 10-year period, vaginal myomectomy was attempted in 46 women with a symptomatic prolapsed pedunculated submucous myoma. The procedure was successful in 43 and failed in three patients, necessitating an abdominal operation. Vaginal myomectomy for this condition was simple and quick, and the postoperative course was usually uneventful. Only 8.8% of 34 patients with a median follow-up of 5.5 years required a repeat vaginal myomectomy, and only 5.9% needed a hysterectomy. Vaginal myomectomy is recommended as the initial treatment of choice for prolapsed pedunculated submucous myoma, except in those cases in which other indications necessitate an abdominal approach.

Cytologic examination of ovarian cyst fluid for the distinction between benign and malignant tumors.

OBJECTIVE: To assess the feasibility of using cytologic examination of ovarian cyst fluid for distinguishing between benign and malignant tumors. METHODS: Cyst fluid was aspirated at surgery in 83 women with benign and 35 women with malignant (25 invasive and ten borderline) ovarian tumors and submitted for routine cytologic examination. RESULTS: The specificity of the cytologic examination was 100%, but the sensitivity and negative predictive value were only 26 and 76%, respectively. CONCLUSION: The low sensitivity and negative predictive value of cytologic cyst fluid examination preclude its use for the distinction between benign and malignant ovarian tumors.

Treatment of pelvic peritoneal cysts by drainage and ethanol instillation.

We performed this study to assess the feasibility and effectiveness of ultrasound-guided drainage and ethanol instillation for the treatment of pelvic peritoneal cysts. Six women had pelvic peritoneal cysts after previous pelvic surgery; when the cysts recurred after simple drainage, the patients underwent transvaginal ultrasound-guided drainage and instillation of 20-30 mL of ethanol into the cyst cavity. All patients except one presented with abdominal pain. All cysts had clinical and ultrasonic benign characteristics. Drainage and ethanol instillation were performed successfully in all patients without severe side effects or complications. After a mean follow-up time of 13.6 months, a recurrence was found in only one patient, who was successfully retreated. These preliminary results indicate that transvaginal ultrasound-guided fluid drainage and ethanol instillation is an effective treatment for pelvic peritoneal cysts.

Cyst fluid CA 125 levels in ovarian epithelial neoplasms.

OBJECTIVE: To assess the feasibility of using cyst fluid CA 125 levels to distinguish between benign and malignant ovarian cystic neoplasms. METHODS: CA 125 levels were measured in ovarian cyst fluid and in serum obtained at surgery in 44 women with ovarian cystic tumors of epithelial origin (25 benign, 12 malignant, and seven borderline). RESULTS: The median cyst fluid CA 125 level in malignant neoplasms (671 U/mL) was higher than in benign tumors (175 U/mL), and 86% of the malignant tumors contained levels higher than 100 U/mL in the cyst fluid, compared with only 62% of the benign tumors. However, these differences were not statistically significant. CONCLUSION: Cyst fluid levels of CA 125 cannot be used to distinguish between benign and malignant ovarian cysts of epithelial origin.

Cerebral embolization and coma after hysterosalpingography with oil-soluble contrast medium.

A case of coma due to embolization after HSG, using oil-soluble contrast medium is presented. The patient was in a comatose state 11 days and then spontaneously regained full consciousness. The safety of oil-contrast medium for HSG is questionable.