Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a "Molecular Second Look".

OBJECTIVES: The objectives of this study were to assess if targeted investigation for tumor-specific mutations by ultradeep DNA sequencing of peritoneal washes of ovarian cancer patients after primary surgical debulking and chemotherapy, and clinically diagnosed as disease free, provides a more sensitive and specific method to assess actual treatment response and tailor future therapy and to compare this "molecular second look" with conventional cytology and histopathology-based findings. METHODS/MATERIALS: We identified 10 patients with advanced-stage, high-grade serous ovarian cancer who had undergone second-look laparoscopy and for whom DNA could be isolated from biobanked paired blood, primary and recurrent tumor, and second-look peritoneal washes. A targeted 56 gene cancer-relevant panel was used for next-generation sequencing (average coverage, >6500×). Mutations were validated using either digital droplet polymerase chain reaction (ddPCR) or Sanger sequencing. RESULTS: A total of 25 tumor-specific mutations were identified (median, 2/patient; range, 1-8). TP53 mutations were identified in at least 1 sample from all patients. All 5 pathology-based second-look positive patients were confirmed positive by molecular second look. Genetic analysis revealed that 3 of the 5 pathology-based negative second looks were actually positive. In the 2 patients, the second-look mutations were present in either the original primary or recurrent tumors. In the third, 2 high-frequency, novel frameshift mutations in MSH6 and HNF1A were identified. CONCLUSIONS: The molecular second look detects tumor-specific evidence of residual disease and provides genetic insight into tumor evolution and future recurrences beyond standard pathology. In the precision medicine era, detecting and genetically characterizing residual disease after standard treatment will be invaluable for improving patient outcomes.

Racial disparities for uterine corpus tumors: changes in clinical characteristics and treatment over time.

BACKGROUND: Black women with endometrial cancer have been more likely to die than white patients. The authors examined factors associated with the poor outcome for black women with uterine corpus tumors and analyzed whether these characteristics have changed over time based on year of diagnosis. METHODS: The authors examined women with uterine neoplasms recorded from 1988-2004 in the Surveillance, Epidemiology and End Results (SEER) Database. The authors developed Cox proportional hazards models to examine the effect of race on survival and stratified women by year of diagnosis into 3 groups: 1988-1993, 1994-1998, 1999-2004. RESULTS: A total of 80,915 patients including 5564 (7%) black women were identified. Black patients were significantly younger, had more advanced stage tumors, and had more aggressive, nonendometrioid histologic variants (P<.001). Black women were 60% more likely to die from their tumors than white women when matched for other prognostic variables (hazards ratio, 1.60; 95% confidence interval, 1.51-1.69). For each of the 3 time periods, survival was worse for blacks even when stratified by stage and histology. Over time, the incidence of serous and clear-cell tumors increased, and the use of radiation decreased for both races. Staging lymphadenectomy was performed more commonly in both blacks (45%) and whites (48%) who had been treated more recently. CONCLUSIONS: Black women with uterine corpus tumors were more likely to die from their disease. This survival difference has persisted over time. The clinical characteristics of blacks and whites have remained relatively constant. The proportion of women who undergo surgical staging has increased with time and was well matched between races.

Optimizing the management of stage II endometrial cancer: the role of radical hysterectomy and radiation.

OBJECTIVE: The optimal management of stage II endometrial cancer remains uncertain. We examined the role of radical hysterectomy and adjuvant radiotherapy for stage II endometrial cancer. STUDY DESIGN: The Surveillance, Epidemiology, and End Results database was used to identify 1577 women with stage II endometrioid type endometrial adenocarcinoma who underwent surgical staging. RESULTS: The cohort included 1198 women who underwent simple hysterectomy (76%) and 379 who underwent radical hysterectomy (24%). Radical hysterectomy had no effect on survival (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.61-1.23). Patients who did not receive radiation were 48% (HR, 1.48; 95% CI, 1.14-1.93) more likely to die than those who underwent adjuvant radiotherapy. The survival benefit from radiation was most pronounced in women who underwent radical hysterectomy. CONCLUSION: Adjuvant radiation improves survival. Although the routine performance of radical hysterectomy does not appear to be justified, patients with high-risk stage II tumors appear to benefit from combination therapy with radical hysterectomy and radiotherapy.

Improved survival for fallopian tube cancer: a comparison of clinical characteristics and outcome for primary fallopian tube and ovarian cancer.

BACKGROUND: Fallopian tube cancers are rare neoplasms. These malignancies are thought to behave biologically and clinically like ovarian cancer. The purpose of this study was to compare the clinical behavior and outcome of fallopian tube and ovarian cancer. METHODS: The Surveillance, Epidemiology, and End Results database was reviewed to identify women with tumors of the fallopian tube (FT) and ovary (OV) diagnosed between 1988 and 2004. Demographic and clinical data were compared, and the impact of tumor site on survival was analyzed using Cox models and the Kaplan-Meier method. RESULTS: A total of 55,825 patients were identified, 1576 (3%) with FT and 54,249 (97%) with OV cancer. FT patients were more likely to present with early stage tumors (P < .001). Among FT patients, 47% had stage I/II tumors compared with 29% of OV cancers. In an adjusted Cox model of all patients, cancer-specific mortality was 48% lower in FT patients (hazard ratio, 0.52; 95% confidence interval [CI], 0.48-0.56) compared with OV cancer. Among patients with FT tumors, advanced age and stage were independent predictors of decreased survival. When stratified by stage, survival was similar for stage I and II tumors, but stage III and IV FT patients had an improved survival. The 5-year survival for stage III FT cancer was 54% (95% CI, 48%-60%), compared with 30% (95% CI, 29%-31%) for OV. CONCLUSIONS: Fallopian tube cancers present earlier and at advanced stage have a better overall survival than primary ovarian malignancies. Future clinical trials should recognize the possible distinct clinical behavior of fallopian tube cancers.

Early metastatic spread after a complete response in locally advanced vulvar cancer treated with neoadjuvant chemoradiation: a case report.

BACKGROUND: Preoperative chemoradiation for advanced vulvar cancer reduces the tumor size and decreases morbidity from operative resection. CASE: A woman with locally advanced vulvar cancer had no evidence of metastatic disease at presentation. She displayed complete resolution of her vulvar and groin disease but developed early metastatic spread to the lungs and bone. CONCLUSION: Despite excellent local control, patients with locally advanced vulvar cancer are at risk for early metastatic spread. The effect of delayed surgical intervention, ifany, is unknown.

The utility and cost effectiveness of preoperative computed tomography for patients with uterine malignancies.

OBJECTIVE: To determine the utility and cost effectiveness of preoperative computed tomography (CT) in detecting disease extent in patients with uterine carcinoma. METHODS: Medical records of 762 patients with uterine malignancies at hysterectomy from 1990-2006 were reviewed. Study inclusion required preoperative abdominal-pelvic CT scan. All CT findings were correlated with intraoperative and pathologic data. Statistical analysis was performed using Fisher's exact test. Cost analysis was based on Medicare fee schedules. RESULTS: 250 subjects (33%), who underwent preoperative CT, comprised the study cohort. CT suggested metastases in 22 (9%) cases and altered management in 7 (3%). Incidental findings were noted in 43 cases (17%), and altered management in 7 (3%). Among complex atypical hyperplasia (CAH) and grade 1 endometrioid cancers, CT suggested metastases in 9% and demonstrated other incidental findings in 21%; management was altered in just 4% of patients. Similarly, among grade 2/3 endometrioid tumors, CT suggested metastases in 7%, and incidental findings in 14%; management was altered in 4% of cases. For high-risk histologies, CT altered management in 11% of papillary serous and clear cell cases and in 13% of sarcomas. CT findings more often altered management in women with high-risk histologies than in those with endometrioid carcinomas (p=0.05). Expenditure of $17,622 for CT imaging is required to alter management of one patient. CONCLUSIONS: Preoperative CT is costly, and rarely alters management in patients with uterine neoplasms, particularly among endometrioid carcinomas. CT may be beneficial in patients with high-risk histologies and requires further study.

Natural history of established low grade cervical intraepithelial (CIN 1) lesions.

UNLABELLED: THE AIM of the present study was to ascertain the natural history of cervical intraepithelial lesions 1 (CIN 1) and to develop recommendations to optimize follow-up. PATIENTS AND METHODS: Patients referred for colposcopy from January, 1996 to July, 2005 were reviewed. A prospectively maintained database was quarried for demographic, clinical, and pathologic data. RESULTS: The cohort included 1,001 patients with CIN 1. At 6 months, 330 patients (49%) regressed to normal, 305 (45%) had persistent low grade, while 45 (7%) progressed to high grade lesions. At 12 months, of those with negative pathology at 6 months, 200 (80%) remained negative, 42 (16%) demonstrated low grade and 9 (4%) progressed to high grade lesions. Of those with low grade lesions at 6 months, 131 (50%) regressed, 121 (46%) had persistent low grade, and 10 (4%) progressed to high grade lesions. CONCLUSION: Our data demonstrates a low rate of progression for CIN 1, suggesting it may be reasonable to prolong the screening interval in women with CIN 1.

Uterine carcinosarcomas and grade 3 endometrioid cancers: evidence for distinct tumor behavior.

OBJECTIVE: To compare the clinical behavior and outcome of uterine carcinosarcomas and grade 3 endometrioid carcinomas. METHODS: Data on patients with grade 3 endometrioid adenocarcinomas and uterine carcinosarcomas, from 1988 to 2004, was obtained from the Surveillance, Epidemiology, and End Results database. Mortality was analyzed using Cox proportional hazards models. Survival analysis was performed with the Kaplan-Meier method and log rank test. RESULTS: The cohort included 8,986 women with 5,024 (56%) grade 3 endometrioid carcinomas and 3,962 (44%) uterine carcinosarcomas. Women with uterine carcinosarcomas were older (aged 70 years compared with 66 years; P<.001) and more often nonwhite (23% compared with 15%; P<.001). These women presented with more advanced disease (stage III/IV 41% compared with 31%; P<.001). Multivariable analysis demonstrated that uterine carcinosarcoma histology, advanced age, nonwhite race, and advanced stage were independent predictors of poor survival. Cancer-specific mortality was 45% lower in women with grade 3 endometrioid carcinomas (hazard ratio 0.55; 95% confidence interval [CI] 0.5-0.6). The 5-year cancer-specific survival was lower for women with uterine carcinosarcoma for each disease stage. Survival for stage IC was 38% (95% CI 33-45%) for uterine carcinosarcoma compared with 68% (95% CI 63-73%) for grade 3 endometrioid carcinoma. For stage III, survival was 22% (95% CI 19-26%) for uterine carcinosarcoma compared with 45% (95% CI 41-49%) for grade 3 endometrioid carcinoma. CONCLUSION: Carcinosarcomas present at more advanced stage and have worse survival than grade 3 endometrioid carcinomas. Carcinosarcomas may represent a distinct biologic entity. LEVEL OF EVIDENCE: II.

The role of radiation in improving survival for early-stage carcinosarcoma and leiomyosarcoma.

OBJECTIVE: We examined the effect of radiation on survival for early-stage uterine carcinosarcomas and leiomyosarcomas. STUDY DESIGN: The surveillance, epidemiology, and end results database was used to identify patients with stage I/II carcinosarcomas and leiomyosarcomas. Logistic regression and Cox models were developed to determine radiation use and survival. RESULTS: Among 1819 women with carcinosarcomas and 1088 women with leiomyosarcomas, radiation was administered to 667 of the patients (37%) with carcinosarcomas and to 235 of the patients (22%) with leiomyosarcomas. In a multivariate model, adjuvant radiation reduced the risk of death by 21% in women with carcinosarcomas (hazard ratio, 0.79; 95% CI, 0.7-0.9). Radiation reduced mortality rates in patients with carcinosarcomas who had not undergone node dissection but had only a marginal effect on survival in node-negative women. Adjuvant radiation had no effect on survival for early-stage leiomyosarcomas (hazard ratio, 1.1; 95% CI, 0.9-1.4). CONCLUSION: Adjuvant radiotherapy improves survival for select patients with early-stage carcinosarcomas but is of limited value for leiomyosarcomas.

The utility of preoperative endometrial sampling for the detection of uterine sarcomas.

OBJECTIVE: Uterine sarcomas are aggressive cancers, often not recognized prior to surgical exploration. The goal of this study was to determine the utility of endometrial sampling in detecting uterine sarcomas and to examine factors associated with diagnostic inaccuracy. METHODS: All uterine tumors identified at hysterectomy from 1990 to 2006 were reviewed. Included patients underwent preoperative endometrial sampling reviewed at our center. Pathologic data was documented through review of hospital records. Statistical analysis was performed using Chi square test. RESULTS: 938 patients were identified. Preoperative sampling was available for review in 730 (78%) subjects. Uterine sarcomas occurred in 142 patients; 72 (51%) underwent preoperative sampling. Overall, endometrial sampling identified an invasive tumor in 84% (600/713), and the correct histology in 79% (564/713). Among women with sarcomas, preoperative sampling suggested an invasive tumor in 86% (62/72) and predicted the correct histologic diagnosis in 64% (46/72). The rate of detection of an invasive cancer by preoperative sampling was not statistically different among sarcomas and epithelial tumors (86% vs. 84%, p=0.76). Preoperative sampling was significantly less reliable in predicting the correct histology for uterine sarcomas (64% vs. 81%, p<0.0001). Similar trends were seen when sarcoma patients were compared to low-grade and high-grade epithelial cancers. Both biopsy and curettage had similar accuracy in diagnosing sarcomas (p=0.84). CONCLUSIONS: Endometrial sampling has a significantly lower predictive value in diagnosing uterine sarcomas compared to epithelial uterine malignancies. Biopsy and curettage have similar accuracy. Novel diagnostic techniques are needed to accurately identify uterine sarcomas preoperatively.

Analysis of survival after laparoscopic management of endometrial cancer.

STUDY OBJECTIVE: To assess the effect of laparoscopic surgery on the survival of women with early-stage endometrial cancer and to analyze the factors that affect survival. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Tertiary teaching hospital. PATIENTS: Women with clinical stage I and II endometrial cancer (International Federation of Gynecology and Obstetrics staging, 1971) from January 1993 through June 2003. INTERVENTION: Demographic, surgical, perioperative, and pathologic characteristics of women treated with laparoscopy or laparotomy were compared by use of Fisher's exact test or the Student t test. Recurrence-free and overall survival was calculated by use of the Kaplan-Meier method. Stratified analyses were performed with the log-rank test for factors affecting survival (surgical stage, histologic study, and grade). MEASUREMENTS AND MAIN RESULTS: Sixty-seven and 127 women were treated with laparoscopy and laparotomy, respectively. Median follow-up was 36.3 months for the laparoscopy group and 29.6 months for the laparotomy group. The complication rates in the 2 groups were comparable. Women undergoing laparoscopy had shorter hospital stay and less morbidity related to infection. The 2- and 5-year estimated recurrence-free survival rates for the laparoscopy and laparotomy groups (93 % vs 91.7% and 88.5% vs 85%, respectively), as well as the overall 2- and 5-year survival rates (100% vs 99.2% and 100% vs 97%, respectively) were similar. CONCLUSIONS: Laparoscopic surgery in women with early-stage endometrial carcinoma resulted in survival rates similar to laparotomy, although a small sample size precludes definitive conclusions. A larger randomized comparison of the 2 techniques is needed to validate these findings.

A midpoint assessment of the American Cancer Society challenge goal to decrease cancer incidence by 25% between 1992 and 2015.

In 1998, the American Cancer Society (ACS) set a challenge goal for the nation to reduce cancer incidence by 25% over the period between 1992 and 2015. This report examines the trends in cancer incidence between 1992 and 2004. Trends were calculated using data on incident malignant cancer cases from the Surveillance, Epidemiology, and End Results (SEER) Registry. Delay-adjusted incidence trends for all cancer sites; all cancer sites without prostate cancer included; all cancer sites stratified by gender, age, and race; and for 20 selected cancer sites are presented. Over the first half of the ACS challenge period, overall cancer incidence rates have declined by about 0.6% per year. The greatest overall declines were observed among men and among those aged 65 years and older. The pace of incidence reduction over the first half of the ACS challenge period was only half that necessary to put us on target to achieve the 25% cancer incidence reduction goal in 2015. New understandings of preventable factors are needed, and new efforts are also needed to better act on our current knowledge about how we can prevent cancer, especially by continuing to reduce tobacco use and beginning to reverse the epidemic of obesity.

Laparoscopic lymphadenectomy for gynecologic malignancies using ultrasonically activated shears: analysis of first 100 cases.

OBJECTIVE: To evaluate the feasibility, safety and utility of the ultrasonic shears for laparoscopic pelvic and para-aortic lymph node retrieval in the treatment of gynecologic cancers. METHODS: Data on laparoscopic lymphadenectomy performed for gynecologic malignancies using ultrasonic shears over a 5-year period were collected and analyzed prospectively. RESULTS: Laparoscopic lymphadenectomy using ultrasonic shears was performed on 100 patients with a median age of 58 (17-87) years. The types of malignancies included cervical (n = 29), endometrial (n = 48), ovarian (n = 15), fallopian tube (n = 2), malignant mixed mesodermal tumor (n = 2), vaginal (n = 2) and synchronous ovarian and endometrial cancers (n = 2). Sites of lymphadenectomy included pelvic (n = 49), para-aortic (n = 30) or both pelvic and para-aortic (n = 21). The median nodal yield was 22 (0-87). 66/100 were complete lymphadenectomies with a median nodal yield of 28 (2-71). The median length of hospital stay was 2 (1-13) days and the average blood loss was 148 (0-500) ml. Overall complication rate was 13%. There were 3 intra-operative complications, which were all managed laparoscopically. There were no unplanned conversions to laparotomy. There were 10 post-operative complications including port-site metastasis in a patient with positive nodes (n = 1), trocar-site hernia requiring a second laparoscopy (n = 1), deep leg vein thrombosis (n = 1), and a small bowel obstruction (n = 1). CONCLUSIONS: This is the largest series to date demonstrating the safety and efficacy of ultrasonic shears in laparoscopic lymphadenectomy for gynecologic malignancies. In addition to the potential for lowering the risk for tissue damage, ultrasonic shears offer multifunctionality which allows for a simpler technique with the use of fewer instruments.

Immunohistochemical detection of glucose transporter GLUT1 in benign and malignant fallopian tube epithelia, with comparison to ovarian carcinomas.

CONTEXT: Enhanced expression of GLUT1, a facilitative glucose transporter found on red blood cells, blood-brain barrier, and perineurium, has been described in a large spectrum of epithelial malignancies. OBJECTIVE: We present an immunohistochemical survey of GLUT1 expression in benign and malignant fallopian tube epithelia, and compare serous carcinomas of the fallopian tube and ovary. DESIGN: One hundred two routinely fixed and processed archival specimens (36 benign fallopian tubes, 29 primary tubal adenocarcinomas, and 37 primary ovarian adenocarcinomas) were immunostained with rabbit anti-GLUT1 and developed with streptavidin-biotin/diaminobenzidine. Only distinct membrane staining was scored positively (1+ to 3+). RESULTS: Benign tubes (n = 36) were either negatively stained (58.3%) or displayed rare weak staining (0.5+ to 1+, rarely 2+; 41.7%); of the latter, 4 specimens showed chronic salpingitis, and 6 showed hyperplasia (epithelial tufting and stratification). A case of florid hyperplasia with atypia in a BRCA1-positive patient was GLUT1 negative. Twenty-three (79.3%) of 29 tubal carcinomas were positively stained. Staining ranged from focal/scattered foci (n = 15) to multifocal/extensive (n = 8). Of the 6 nonstaining tubal carcinomas, 3 were undifferentiated. Nineteen tubal carcinoma sections showed residual benign epithelium, which was consistently nonstaining. Very frequently, GLUT1 staining intensified in cells furthest from stroma/ stromal capillaries and/or bordering necrotic zones. On average, GLUT1 staining in primary fallopian tube cancers was less extensive than in primary ovarian adenocarcinomas. CONCLUSIONS: GLUT1 immunostaining of fallopian tube adenocarcinomas was substantially stronger and more extensive than staining of benign tubal epithelium, consistent with previously described findings in carcinomas versus benign tissues from many primary sites. The frequent localization of GLUT1 positivity to regions most distal from stroma/stromal capillaries is consistent with known activation of GLUT1 expression by hypoxia-sensing cellular pathways and may constitute a survival advantage under hypoxic conditions present in malignancy. The difference in extent of GLUT1 staining between primary tubal and primary ovarian serous adenocarcinomas is discussed.

The incidence of port-site metastases in gynecologic cancers.

OBJECTIVES: To determine the incidence of port-site metastases in patients undergoing laparoscopic procedures for gynecologic cancers. METHODS: The charts of patients treated by laparoscopy for diagnosis, treatment, or staging of gynecologic cancers by the academic faculty attending physicians were studied from July 1, 1997 to June 30, 2001. No patient without a histological or cytological diagnosis of cancer from the index procedure were included. Fisher's exact test was used for statistical analysis. RESULTS: Eighty-three patients were identified accounting for 87 procedures. Types of cancer treated included endometrial (39), ovarian (29), and cervical (14). Twenty procedures were performed for recurrence of ovarian or peritoneal cancer, and ascites was present in 10 cases. Port-site metastases occurred in 2 patients accounting for 8 sites. Five sites were diagnosed in a single patient 13 days after a second-look laparoscopy for stage IIIB ovarian cancer, and 3 sites were diagnosed in a patient 46 days after an interval laparoscopy for stage IIIC primary peritoneal cancer. Ascites was present in both patients. The overall incidences of port-site metastases per procedure and per port placed were 2.3% (2/87) and 2.4% (8/330), respectively. In patients with a recurrence of ovarian or peritoneal cancer, no port-site metastases (0/16) occurred in the absence of ascites, whereas 50% (2/4) of patients with ascites developed port-site metastases (P < .035). CONCLUSIONS: The overall incidence of port-site metastases in gynecologic cancers in our study was 2.3%. The risk of port-site metastases is highest (5%) in patients with recurrence of ovarian or primary peritoneal malignancies undergoing procedures in the presence of ascites.

Prophylactic oophorectomy: a morphologic and immunohistochemical study.

BACKGROUND: The tumorigenesis of ovarian carcinoma is poorly understood. The authors studied morphologic features and immunohistochemical expression patterns of neoplasia-associated markers in prophylactically removed ovaries, normal ovaries, and papillary serous ovarian carcinomas to identify possible preneoplastic changes in ovarian surface epithelium. METHODS: Morphologic features and immunohistochemical expression patterns of CA-125, Ki-67, p53, E-cadherin, and Bcl-2 were evaluated in 21 normal ovaries, 31 ovaries that were removed prophylactically for increased carcinoma risk, and 7 ovarian papillary serous carcinomas. Representative slides from formalin-fixed, paraffin-embedded tissue blocks were submitted to immunohistochemical staining and were evaluated independently by three gynecologic pathologists. For statistical analyses, Fisher exact tests, multivariate analyses, Spearman rank correlation coefficients, Wald statistics, Kruskal-Wallis tests, and Mann-Whitney tests were used. Immunohistochemical staining results were correlated with morphologic findings. RESULTS: The authors found progressive increases in reactivity with the lowest expression in normal ovarian epithelium, stronger expression in epithelium from prophylactically removed ovaries, and the highest expression in carcinomas for Ki-67 and p53. A similar trend was observed for CA-125. Positivity for Ki-67 and p53 was seen predominantly in the epithelium of inclusion cysts and deep invaginations, including those areas that had been identified as hyperplastic or dysplastic on routine hematoxylin and eosin-stained sections. CONCLUSIONS: The current results suggest biologic/molecular evidence for the existence of preneoplastic changes in ovarian surface epithelium and support the previously proposed concept of ovarian dysplasia. Subtle morphologic alterations of the ovarian epithelium may be biologically significant.

American cancer society guideline for the early detection of cervical neoplasia and cancer.

An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical neoplasia and cancer, based on recommendations from a formal review and recent workshop, is presented. The new screening recommendations address when to begin screening, when screening may be discontinued, whether to screen women who have had a hysterectomy, appropriate screening intervals, and new screening technologies, including liquid-based cytology and HPV DNA testing.

American Cancer Society guideline for the early detection of cervical neoplasia and cancer.

An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical neoplasia and cancer, based on recommendations from a formal review and recent workshop, is presented. The new screening recommendations address when to begin screening, when screening may be discontinued, whether to screen women who have had a hysterectomy, appropriate screening intervals, and new screening technologies, including liquid-based cytology and HPV DNA testing.

Comparative immunohistochemical studies of bcl-2 and p53 proteins in benign and malignant ovarian endometriotic cysts.

BACKGROUND: A number of histologic and epidemiologic studies have suggested an association between endometriosis and ovarian carcinoma. Some reports have described a transition from endometriosis to atypical endometriosis to carcinoma. Using immunohistochemistry, the authors compared staining patterns in benign endometriotic cysts with ovarian tumors and the endometriotic cyst lining from which they arose, in an attempt to identify sequential or etiologic correlations. METHODS: One hundred thirteen formalin-fixed, paraffin-embedded sections were studied (30 benign ovarian endometriotic cysts, 24 endometriotic cysts containing endometrioid carcinomas, 19 endometriotic cysts harboring clear cell carcinomas, and 40 ovarian papillary serous cystadenocarcinomas). All sections were immunostained with anti-bcl-2 and anti-p53 antibodies using the streptavidin-biotin method. RESULTS: bcl-2 was reported to stain 23% of benign endometriotic cysts, 67% of endometrioid carcinomas, 73% of clear cell carcinomas, and 50% of papillary serous carcinomas. Approximately 42% of benign endometriotic lesions adjacent to the endometrioid carcinoma and 73% adjacent to clear cell carcinomas were found to stain for bcl-2 (p = 0.274 [not significant (NS)] and P = 0.008, respectively). p53 staining was negative in the benign endometriotic cyst group and was positive in 37-55% of the group with tumors. p53 staining was positive in 25% of the benign endometriotic lesions next to the endometrioid carcinoma and in 9% of the benign endometriotic lesions next to clear cell carcinoma (P = 0.014 and P = 0.239 [NS], respectively). CONCLUSIONS: The results of the current study suggest that alterations in bcl-2 and p53 may be associated with the malignant transformation of endometriotic cysts.