Michael G. Muto

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.

Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1.

BACKGROUND We tested the hypothesis that ovarian cancers associated with germ-line mutations of BRCA1 have distinct clinical and pathological features as compared with sporadic ovarian cancers. METHODS We reviewed clinical and pathological data on patients with primary epithelial ovarian cancer found to have germ-line mutations of BRCA1. Survival among patients with advanced-stage cancer and such mutations was compared with that in control patients matched stage, grade, and histologic subtype of the tumors. A combination of single-strand conformation and sequencing analyses was used to examine the 22 coding exons and intronic splice-donor and splice-acceptor regions of BRCA1 for mutations in pathological specimens. Alternatively, some patients were known to be obligate carriers of the mutant BRCA1 gene because of their parental relationships with documented mutant-gene carriers. RESULTS We identified 53 patients with germ-line mutations of BRCA1. The average age at diagnosis was 48 years (range, 28 to 78). Histologic examination in 43 of the 53 patients showed serous adenocarcinoma. Thirty-seven tumors were of grade 3, 11 were of grade 2, 2 were of grade 1, and 3 were of low malignant potential. In 38 patients, the tumors were of stage III; 9 patients (including those with tumors of low malignant potential) had stage I disease, 5 had stage IV, and 1 had stage II. As of June 1996, with a median follow-up among survivors of 71 months from diagnosis, 20 patients had died of ovarian cancer, 27 had no evidence of the disease, 4 were alive with the disease, and 2 had died of other diseases. Actuarial median survival for the 43 patients with and advanced-stage disease was 77 months, as compared with 29 months for the matched controls (P<0.001). CONCLUSIONS As compared with sporadic ovarian cancers, cancers associated with BRCA1 mutation appear to have a significantly more favorable clinical course.

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.

The distal fallopian tube: a new model for pelvic serous carcinogenesis.

Purpose of review Research over the past 50 years has yielded little concrete information on the source of pelvic serous cancer in women, creating a knowledge gap that has adversely influenced our ability to identify, remove or prevent the earliest stages of the most lethal form of ovarian cancer. Recent findings The distal fallopian tube is emerging as an established source of many early serous carcinomas in women with BRCA mutations (BRCA+). Protocols examining the fimbrial (SEE-FIM) end have revealed a noninvasive but potentially lethal form of tubal carcinoma, designated tubal intraepithelial carcinoma. Tubal intraepithelial carcinoma is present in many women with presumed ovarian or peritoneal serous cancer. A candidate precursor to tubal intraepithelial carcinoma, entitled the ‘p53 signature’, suggests that molecular events associated with serous cancer (p53 mutations) may be detected in benign mucosa. Summary A fully characterized precursor lesion is a first and necessary step to pelvic serous cancer prevention. The emerging data offer compelling evidence for a model of ‘fimbrial-ovarian’ serous neoplasia, and call attention to the distal fallopian tube as an important source for this disease, the study of which could clarify pathways to cancer in both organs and generate novel strategies for cancer prevention.

Serous Tubal Intraepithelial Carcinoma: Its Potential Role in Primary Peritoneal Serous Carcinoma and Serous Cancer Prevention

PURPOSE A diagnosis of primary peritoneal serous carcinoma (PPSC) requires exclusion of a source in other reproductive organs. Serous tubal intraepithelial carcinoma (STIC; stage 0) has been described in asymptomatic women with BRCA mutations and linked to a serous cancer precursor in the fimbria. This study examined the frequency of STIC in PPSC and its clinical outcome in BRCA-positive women. PATIENTS AND METHODS Presence or absence of STIC was recorded in consecutive cases meeting the 2001 WHO criteria for PPSC, including 26 patients with nonuniform sampling of the fallopian tubes (group 1) and 19 patients with complete tubal examination (group 2; sectioning and extensively examining the fimbriated end, or SEE-FIM protocol). In selected cases, STIC or its putative precursor and the peritoneal tumor were analyzed for p53 mutations (exons 1 to 11). Outcome of STIC was ascertained by literature review. RESULT Thirteen (50%) of 26 PPSCs in group 1 involved the endosalpinx, with nine STICs (35%). Fifteen (79%) of 19 cases in group 2 contained endosalpingeal involvement, with nine STICs (47%). STIC was typically fimbrial and unifocal, with variable invasion of the tubal wall. In five of five cases, the peritoneal and tubal lesion shared an identical p53 mutation. Of 10 reported STICs in BRCA-positive women, all patients were without disease on follow-up. CONCLUSION The fimbria is the source of nearly one half of PPSCs, suggesting serous malignancy originates in the tubal mucosa but grows preferentially at a remote peritoneal site. The generally low risk of recurrence in stage 0 (STIC) disease further underscores STIC as a possible target for early serous cancer detection and prevention.

Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy

Chemoresistance to platinum therapy is a major obstacle that needs to be overcome in the treatment of ovarian cancer patients. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). This study demonstrates that the Notch signaling pathway and Notch3 in particular are critical for the regulation of CSCs and tumor resistance to platinum. We show that Notch3 overexpression in tumor cells results in expansion of CSCs and increased platinum chemoresistance. In contrast, γ-secretase inhibitor (GSI), a Notch pathway inhibitor, depletes CSCs and increases tumor sensitivity to platinum. Similarly, a Notch3 siRNA knockdown increases the response to platinum therapy, further demonstrating that modulation of tumor chemosensitivity by GSI is Notch specific. Most importantly, the cisplatin/GSI combination is the only treatment that effectively eliminates both CSCs and the bulk of tumor cells, indicating that a dual combination targeting both populations is needed for tumor eradication. In addition, we found that the cisplatin/GSI combination therapy has a synergistic cytotoxic effect in Notch-dependent tumor cells by enhancing the DNA-damage response, G2/M cell-cycle arrest, and apoptosis. Based on these results, we conclude that targeting the Notch pathway could significantly increase tumor sensitivity to platinum therapy. Our study suggests important clinical applications for targeting Notch as part of novel treatment strategies upon diagnosis of ovarian cancer and at recurrence. Both platinum-resistant and platinum-sensitive relapses may benefit from such an approach as clinical data suggest that all relapses after platinum therapy are increasingly platinum resistant.

Occult Ovarian Tumors in Women With BRCA1 or BRCA2 Mutations Undergoing Prophylactic Oophorectomy

PURPOSE To review the findings at prophylactic oophorectomy of a series of women who presented to a familial breast and ovarian cancer clinic. MATERIALS AND METHODS Data from medical charts, operative notes, and pathology reports were collected on women who had undergone prophylactic oophorectomies because of the elevated risk of ovarian cancer. Because only a subset of patients underwent BRCA1 and BRCA2 testing, each patients risk of hereditary predisposition was calculated using the Berry-Parmigiani model and family history data. RESULTS From June 1989 to December 1998, 50 women seen at our clinic underwent prophylactic oophorectomy, 33 of whom had a calculated risk of carrying a germline BRCA1 or BRCA2 mutation greater than 25%. Among this group, four incidental tumors were found (four of 33, or 12%); one tumor was noted at the time of surgery and three were noted only in the final pathology. Two patients had microscopic, poorly differentiated serous adenocarcinomas in multiple sites on both ovaries. A third patient had a bilateral serous borderline tumor with micropapillary features. The fourth patient had a microscopic serous borderline ovarian tumor. All four patients had germline BRCA1 or BRCA2 mutations, and three had unremarkable transvaginal ultrasonography examinations within 6 months before prophylactic surgery. CONCLUSION Foci of malignant tumor are not uncommon in prophylactic oophorectomies performed in women at very high risk for ovarian cancer and may not be detected on ultrasonograms. Surgeons should have a high suspicion of finding cancer in these women at the time of prophylactic surgery, and careful pathologic assessment of the specimens should be conducted.

Advances in the recognition of tubal intraepithelial carcinoma: applications to cancer screening and the pathogenesis of ovarian cancer.

Prophylactic salpingo-oophorectomies from women with BRCA mutations (BRCA+) have identified the tube as a frequent site of early pelvic serous carcinoma (tubal intraepithelial carcinoma [TIC]). These observations have implications for both the early recognition of pelvic serous carcinoma in susceptible women and determining the ultimate site of origin for pelvic serous carcinomas. Moreover, the unique pathology of TIC has shifted attention from the more exuberant proliferations mentioned in prior studies to a spectrum of neoplastic atypias that can be morphologically subtle. This review addresses a multitude of epithelial changes; benign, malignant, and an intriguing third group, which we term “p53 signatures,” is found in benign, nonciliated epithelium and stain intensely positive for p53. Understanding all 3 is important for the proper management of women undergoing prophylactic salpingo-oophorectomy and possibly formulating an integrated model for the pathogenesis of serous carcinoma in the reproductive tract. A protocol for sectioning and extensively examining the fimbriated end (SEE-FIM), and its rationale, is described.

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.