Colleen M. Feltmate

Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship.

Proposed origins of pelvic serous carcinoma include the ovary, fallopian tube, and peritoneum. Prophylactic salpingo-oophorectomies in BRCA+ women have recently identified the fimbria as a site of origin for early serous carcinoma (tubal intraepithelial carcinoma or TIC). We explored the relationship of TIC to pelvic serous carcinomas in consecutive cases with complete adnexal exam (SEE-FIM protocol). Cases positive (group A) or negative (group B) for endosalpinx (including fimbria) involvement, were subclassified as tubal, ovarian, or primary peritoneal in origin. Coexisting TIC was recorded in group A when present and p53 mutation status was determined in 5 cases. Of 55 evaluable cases, 41 (75%) were in group A; including tubal (n=5), peritoneal (n=6), and ovarian (n=30) carcinomas. Foci of TIC were identified in 5 of 5, 4 of 6, and 20 of 30, respectively. Ninety-three percent of TICs involved the fimbriae. Five of 5 TICs and concurrent ovarian carcinomas contained identical p53 mutations. Thirteen of 14 cases in group B were classified as primary ovarian carcinomas, 10 with features supporting an origin in the ovary. Overall, 71% and 48% of “ovarian” serous carcinomas had endosalpinx involvement or TIC. TIC coexists with all forms of pelvic serous carcinoma and is a plausible origin for many of these tumors. Further studies are needed to elucidate the etiologic significance of TIC in pelvic serous carcinoma, reevaluate the criteria for tubal, peritoneal, and ovarian serous carcinoma, and define the role of the distal tube in pelvic serous carcinogenesis.

The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome.

A proportion of adenocarcinomas in prophylactic adnexectomies (bilateral salpingo-oophorectomies [BSOs]) from women with BRCA mutations (BRCA positive) occur in the fallopian tube. We analyzed a consecutive series of BSOs from BRCA-positive women following an index case of fimbrial serous carcinoma. To determine if the fimbria is a preferred site of origin, we followed a protocol for Sectioning and Extensively Examining the FIMbria (SEE-FIM). Immunostaining for p53 and Ki-67 was also performed. Thirteen BRCA-positive women (cases) and 13 women undergoing BSOs for other disorders (controls) were studied. Tubal carcinoma was detected in 4 cases at the initial histologic evaluation and in no controls. A fifth carcinoma was discovered following further sectioning of the fimbriae. Three were BRCA2 positive and two BRCA1 positive. Three were in the fimbria, one in both the fimbria and proximal tube, and one involved the ampulla. Four were serous carcinomas, four were confined to the tube, and three were noninvasive (intraepithelial). No ovarian carcinomas were identified. All tumors were Ki-67 positive (>75% of cell nuclei), and excluding one endometrioid carcinoma, p53 positive (>75% cell nuclei); p53 positivity in the absence of elevated Ki-67 did not correlate with morphologic neoplasia. The fimbria was the most common location for early serous carcinoma in this series of BRCA-positive women. Protocols that extensively examine the fimbria (SEE-FIM) will maximize the detection of early tubal epithelial carcinoma in patients at risk for ovarian cancer. Investigative strategies targeting the fimbriated end of the fallopian tube should further define its role in the pathogenesis of familial and sporadic ovarian serous carcinomas.

Primary Fallopian Tube Malignancies in BRCA-Positive Women Undergoing Surgery for Ovarian Cancer Risk Reduction

PURPOSE To review the frequency and location of malignancies detected after prophylactic salpingo-oophorectomy in women with BRCA mutations. METHODS Medical records and pathology findings were reviewed from BRCA-positive women undergoing prophylactic surgery for ovarian cancer risk reduction who underwent complete examination of the adnexa. Patients undergoing this procedure between January 1999 and January 2007 were identified. RESULTS From January 1999 to January 2007, 122 BRCA-positive patients underwent prophylactic surgery in the Division of Gynecologic Oncology at Brigham and Womens Hospital. The median age was 46.5 years (range, 33 to 76 years). Seven (5.7%) were found to have an early malignancy in the upper genital tract and all patients were age > or = 44 years at diagnosis. Of seven consecutive cancers culled between January 1999 and January 2007, all (100%) originated in the fimbrial or ampullary region of the tube; six had an early (intraepithelial) component. Two were associated with surface implants on the ovary and two required repeated sectioning to detect microscopic carcinomas in the fimbria. CONCLUSION The distal fallopian tube seems to be the dominant site of origin for early malignancies detected in approximately 6% of women undergoing ovarian cancer risk-reduction surgery. The greatest proportion of serous cancer risk in BRCA mutation-positive women should be assigned to the fimbria rather than the ovary, and future clinical and research protocols should employ thorough examination of the fimbria, including multiple sections from each tissue block, to maximize detection of early malignancies in this population.

Robotic versus open radical hysterectomy: A comparative study at a single institution

OBJECTIVE To compare the short-term surgical outcome of patients undergoing robotic radical hysterectomy (RRH) versus open radical hysterectomy (ORH) for the treatment of early stage cervical cancer. METHODS IRB approval was obtained for a retrospective chart review of all radical hysterectomies (RHs) for Stage I and II cervical cancer performed at Brigham and Womens Hospital between August 1, 2004 and August 1, 2007. Prior to August 1, 2006 all procedures were ORHs. After this date, all procedures were RRHs. Demographic data, operative data and short-term outcomes were compared. Statistical analysis using t-tests and Fishers Exact test were performed with SAS software. RESULTS A total of 48 RHs were identified, including 16 RRHs and 32 ORHs. The groups did not differ significantly in age, body mass index, stage, or histology. Mean operative time was significantly longer for RRH than ORH (4:50 vs 3:39 h, p=0.0002). The mean estimated blood loss was significantly less for RRH than ORH (81.9 vs 665.6 mL, p<0.0001). The mean number of lymph nodes resected did not differ between RRHs and ORHs (15.6 vs 17.1, p=0.532). There were no intra-operative complications in the RRH group and one ureteral transection in the ORH group. Three RRH patients (18.8%) suffered post-operative complications which included a vaginal cuff infected hematoma, a transient ureterovaginal fistula, and a pelvic lymphocele, in comparison to seven in the ORH group (21.9%) which included 3 wound infections, two patients with pulmonary emboli, a partial small bowel obstruction with a mesenteric abscess, and a post-operative ileus (p=0.999). Mean length of stay was significantly shorter for the RRH group (1.7 vs. 4.9 days, p<0.0001). CONCLUSION RRH results in lower blood loss and shorter length of stay, compared to ORH. Intra-operative and post-operative complication rates are comparable. RRH is a promising new surgical technique that deserves further study.

Low risk of relapse after achieving undetectable hCG levels in women with partial molar pregnancy

OBJECTIVE: Complete hydatidiform molar pregnancies occur in approximately 1 of 1,000 conceptions. After uterine evacuation of the trophoblastic tissue, women are followed up with serial serum human chorionic gonadotropin (hCG) measurements. Patients are considered to have attained remission when their hCG level spontaneously declines to an undetectable level and remains there during a 6-month follow-up period. This standard effectively detects all disease recurrence; however, it is resource intensive, delays child bearing, and is subject to significant noncompliance. Our objective was to determine the risk of disease recurrence after hCG spontaneously declines to undetectable levels. METHODS: We used a database from the New England Trophoblastic Disease Center to analyze hCG levels in patients with complete molar pregnancies. RESULTS: Among 1,029 women with complete molar pregnancy and complete data, 15% developed persistent gestational trophoblastic neoplasia. The rate of persistent neoplasm among those whose hCG level fell spontaneously to undetectable levels was 0.2% (2/876, 95% confidence interval 0–0.8%). No women developed persistent gestational trophoblastic neoplasia after their hCG level fell to undetectable levels using an assay with a sensitivity of 5 mIU/mL (n = 82, 95% confidence interval 0–4.5%). CONCLUSION: Based on our experience with women with complete hydatidiform molar pregnancies whose hCG values spontaneously fell to undetectable levels after molar evacuation, we conclude that the risk of recurrent neoplasm after hCG levels fall to less than 5 mIU/mL approaches zero. LEVEL OF EVIDENCE: II-2

Gestational trophoblastic disease

Hydatidiform mole, a disorder of fertilization, comprises complete and partial molar pregnancy. The pathologic and clinical features of complete and partial mole are well-described. Because of earlier diagnosis, however, the clinical presentation of complete molar pregnancy has significantly changed in recent years. The earlier diagnosis of complete mole is associated with more subtle pathologic findings than later molar pregnancy. The use of immunohistochemical techniques for the detection of maternally imprinted genes as ancillary testing in the diagnosis of complete and partial mole is therefore increasing. Although most molar pregnancies are sporadic, a familial syndrome of recurrent hydatidiform mole has been described. Further research will hopefully lead to identification of the gene defect responsible for this uncommon syndrome. Fortunately, patients with molar pregnancies can generally anticipate normal future reproduction. Close hCG follow-up after molar pregnancy is required to rule out development of postmolar gestational trophoblastic neoplasia. Recent studies suggest that a shorter period of postmolar follow-up may be reasonable for patients with both complete and partial molar pregnancy.

The Effect of Acute Ethanol Ingestion on Estrogen Levels in Postmenopausal Women Using Transdermal Estradiol

Objective: To determine whether acute alcohol ingestion raises estradiol (E2) and estrone (E1) levels in a randomized, controlled, crossover study on postmenopausal women using transdermal E2. Methods: Healthy, non-smoking postmenopausal women (n = 7) using no medications were enrolled. Transdermal E2, 0.15 mg, was applied 13 hours before the subjects ingested alcohol (1 mL/kg 95% ethanol) or isocaloric carbohydrate punch. Serum samples were obtained for 40 minutes before drink ingestion and 6 hours after drink ingestion and were assayed for E2 and E1. Results: Ethanol levels peaked 60 minutes after the start of ethanol-drink ingestion, at 25.4 mmol/L (117 mg/dL). Estradiol levels rose significantly above the mean baseline of 657 pmol/L (179 pg/mL) after ethanol-drink ingestion (P ≤ .01), with a mean peak of 804 pmol/L (219 pg/mL) 35 minutes after the start of drink ingestion, and were significantly greater than the E2 levels that followed the carbohydrate drink (P ≤ .0001). There were no significant changes in E2 or E1 levels after carbohydrate-drink ingestion. Conclusions: We conclude that ethanol ingestion may acutely raise circulating E2 concentrations in women using transdermal E2.

Expression Profiling of Mucinous Tumors of the Ovary Identifies Genes of Clinicopathologic Importance

Purpose: To elucidate the molecular mechanisms contributing to the unique clinicopathologic characteristics of mucinous ovarian carcinoma, global gene expression profiling of mucinous ovarian tumors was carried out. Experimental Design: Gene expression profiling was completed for 25 microdissected mucinous tumors [6 cystadenomas, 10 low malignant potential (LMP) tumors, and 9 adenocarcinomas] using Affymetrix U133 Plus 2.0 oligonucleotide microarrays. Hierarchical clustering and binary tree prediction analysis were used to determine the relationships among mucinous specimens and a series of previously profiled microdissected serous tumors and normal ovarian surface epithelium. PathwayAssist software was used to identify putative signaling pathways involved in the development of mucinous LMP tumors and adenocarcinomas. Results: Comparison of the gene profiles between mucinous tumors and normal ovarian epithelial cells identified 1,599, 2,916, and 1,765 differentially expressed in genes in the cystadenomas, LMP tumors, and adenocarcinomas, respectively. Hierarchical clustering showed that mucinous and serous LMP tumors are distinct. In addition, there was a close association of mucinous LMP tumors and adenocarcinomas with serous adenocarcinomas. Binary tree prediction revealed increased heterogeneity among mucinous tumors compared with their serous counterparts. Furthermore, the cystadenomas coexpressed a subset of genes that were differentially regulated in LMP and adenocarcinoma specimens compared with normal ovarian surface epithelium. PathwayAssist highlighted pathways with expression of genes involved in drug resistance in both LMP and adenocarcinoma samples. In addition, genes involved in cytoskeletal regulation were specifically up-regulated in the mucinous adenocarcinomas. Conclusions: These data provide a useful basis for understanding the molecular events leading to the development and progression of mucinous ovarian cancer.

Helical computed tomography in differentiating appendicitis and acute gynecologic conditions

OBJECTIVE To determine the accuracy and effect of helical computed tomography (CT) in women clinically suspected of having either appendicitis or an acute gynecologic condition. METHODS One hundred consecutive nonpregnant women suspected of having appendicitis or an acute gynecologic condition prospectively had helical CT. Interpretations were correlated with surgical and pathologic findings (41 cases) and clinical follow-up for at least 2 months (59 cases). The accuracy for confirming or excluding both appendicitis and acute gynecologic conditions was determined. The effect on patient care was determined by comparing pre-CT plans with actual treatment. RESULTS Thirty-two women had appendicitis, 15 had acute gynecologic conditions, 27 had other specific diagnoses, and 26 had nonspecific abdominal pain. For diagnosing appendicitis or acute gynecologic conditions, CT had 100% and 87% sensitivity, 97% and 100% specificity, 94% and 100% positive predictive value, 100% and 98% negative predictive value, and 98% and 98% accuracy, respectively. After CT was done, 36 planned hospital admissions, 25 planned hospital observations, and six planned appendectomies were deferred; six women had alternative surgical procedures on the basis of CT results. One patient had an unnecessary appendectomy on the basis of CT findings. CONCLUSION Helical CT is an excellent imaging option for differentiating appendicitis from most acute gynecologic conditions.

Human chorionic gonadotropin follow-up in patients with molar pregnancy: a time for reevaluation ☆

OBJECTIVE To determine how often patients with molar pregnancy do not complete recommended follow-up and to identify factors that may predict failure to complete human chorionic gonadotropin (hCG) monitoring. This study also sought to determine how often patients with molar pregnancy who do not complete follow-up relapse after attaining at least one undetectable hCG value. METHODS Four hundred randomly selected patients with molar pregnancy were analyzed regarding the serum hCG levels after molar evacuation. Demographic factors were determined for each patient: age, marital status, gravidity, parity, health insurance type, and distance from patient residence to trophoblastic center. RESULTS Recommended hCG follow-up was completed in 63% of the uncomplicated 333 cases (n = 211). Three hundred twenty patients achieved at least one undetectable serum hCG level. Among the 320 patients, 33% achieved undetectable hCG values but did not complete recommended follow-up. However, none had any evidence of relapse. A distance of greater than 20 miles from the patients residence to our center was associated with failure to complete hCG follow-up (P = .001). CONCLUSION Because none of the 320 patients who achieved at least one undetectable hCG level has been diagnosed with gestational trophoblastic tumor relapse, it may be appropriate to reassess the duration of hCG monitoring for patients with molar pregnancy.