Is comprehensive surgical staging needed for thorough evaluation of early-stage ovarian carcinoma?

OBJECTIVE: Patients with ovarian cancer may have occult metastasis at the time of surgery. Our purpose was to determine the prevalence and sites of occult metastasis in epithelial ovarian cancer grossly confined to the ovary and examine the significance of routine omentectomy and peritoneal biopsies as part of a comprehensive staging procedure. STUDY DESIGN: Data were retrospectively abstracted from patients presenting to University of Texas Southwestern Medical Center Hospitals from 1993 through 2009 with ovarian cancer without gross spread beyond the ovary who underwent comprehensive surgical staging. RESULTS: A total of 86 patients with ovarian cancer grossly confined to the ovary who underwent complete surgical staging were identified. Of patients, 29% were upstaged following comprehensive surgical staging; 6% had metastatic disease in uterus and/or fallopian tubes, 6% in lymph nodes, and 17% in peritoneal, omental, or adhesion biopsies. CONCLUSION: Patients with epithelial ovarian cancer should continue to undergo comprehensive surgical staging, since it identifies occult metastasis in a significant number of patients.

Improved survival in non-Ashkenazi Jewish ovarian cancer patients with BRCA1 and BRCA2 gene mutations.

OBJECTIVES: Previous studies report a survival advantage in ovarian cancer patients with Ashkenazi Jewish (AJ) breast cancer gene (BRCA) founder mutations. The purpose of this study was to determine if this association exists in patients with non-Ashkenazi Jewish (non-AJ) BRCA mutations. We also sought to account for "survival bias" by minimizing lead time that may exist between diagnosis and genetic testing. METHODS: Patients with stage III/IV ovarian cancer and a non-AJ BRCA mutation, seen between January 1996 and July 2007, were identified from eight institutions. Patients with sporadic ovarian cancer were compared to similar cases, matched by age, stage, year of diagnosis, and vital status at time interval to BRCA testing. Progression-free (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Multivariate Cox proportional hazards models were calculated for variables of interest. Fisher's exact test and chi-square were also used for analysis. RESULTS: Ninety-five advanced stage ovarian cancer patients with non-AJ BRCA mutations and 183 sporadic controls were analyzed. Compared to sporadic ovarian cancer patients, non-AJ BRCA patients had longer PFS (27.9 months vs. 17.9 months, HR 0.61 [95% CI 0.43-0.86]) and OS (101.7 months vs. 54.3 months, HR 0.43 [95% CI 0.27-0.68]). BRCA status was an independent predictor of PFS and OS. CONCLUSIONS: This multicenter study demonstrates a significant survival advantage in advanced stage ovarian cancer patients with non-AJ BRCA mutations, confirming the previous studies in the Jewish population. This improved survival was evident when accounting for the "survival bias" that coincides with genetic testing.

Secondary cytoreductive surgery for recurrent platinum-sensitive ovarian cancer.

OBJECTIVE: To determine the risks and benefits of secondary cytoreductive surgery for recurrent platinum-sensitive ovarian cancer. METHODS: Data were obtained retrospectively for all women with recurrent platinum-sensitive epithelial ovarian cancer who underwent a second debulking operation between 1998 and 2008 at the University of Texas Southwestern Medical Center. Survival analysis and comparisons were performed using the Kaplan-Meier method, log-rank test, and Cox multivariate proportional hazards model. RESULTS: Optimal secondary cytoreductive surgery (<5mm of residual disease) was achieved in 32 of 40 patients (80%). Nine women (23%) developed major complications. Two variables, residual disease of less than 5mm vs 5mm or greater (median 63 months vs 11 months; P=0.003); and less than 5 vs 5 or more sites of disease relapse (median 63 months vs 22 months; P=0.009), were independently associated with survival and retained prognostic significance on multivariate analysis. CONCLUSIONS: Optimal secondary cytoreductive surgery was associated with a survival advantage and acceptable risks.

Somatic LKB1 mutations promote cervical cancer progression.

Human Papilloma Virus (HPV) is the etiologic agent for cervical cancer. Yet, infection with HPV is not sufficient to cause cervical cancer, because most infected women develop transient epithelial dysplasias that spontaneously regress. Progression to invasive cancer has been attributed to diverse host factors such as immune or hormonal status, as no recurrent genetic alterations have been identified in cervical cancers. Thus, the pressing question as to the biological basis of cervical cancer progression has remained unresolved, hampering the development of novel therapies and prognostic tests. Here we show that at least 20% of cervical cancers harbor somatically-acquired mutations in the LKB1 tumor suppressor. Approximately one-half of tumors with mutations harbored single nucleotide substitutions or microdeletions identifiable by exon sequencing, while the other half harbored larger monoallelic or biallelic deletions detectable by multiplex ligation probe amplification (MLPA). Biallelic mutations were identified in most cervical cancer cell lines; HeLa, the first human cell line, harbors a homozygous 25 kb deletion that occurred in vivo. LKB1 inactivation in primary tumors was associated with accelerated disease progression. Median survival was only 13 months for patients with LKB1-deficient tumors, but >100 months for patients with LKB1-wild type tumors (P = 0.015, log rank test; hazard ratio = 0.25, 95% CI = 0.083 to 0.77). LKB1 is thus a major cervical tumor suppressor, demonstrating that acquired genetic alterations drive progression of HPV-induced dysplasias to invasive, lethal cancers. Furthermore, LKB1 status can be exploited clinically to predict disease recurrence.

Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas.

Mutations in the LKB1 tumor suppressor gene result in the Peutz-Jeghers syndrome, an autosomal dominant condition characterized by hamartomatous polyps of the gastrointestinal tract and a dramatically increased risk of epithelial malignancies at other sites, including the female reproductive tract. Here we show that female mice heterozygous for a null Lkb1 allele spontaneously develop highly invasive endometrial adenocarcinomas. To prove that these lesions were indeed due to Lkb1 inactivation, we introduced an adenoviral Cre vector into the uterine lumen of mice harboring a conditional allele of Lkb1. This endometrial-specific deletion of the Lkb1 gene provoked highly invasive and sometimes metastatic endometrial adenocarcinomas closely resembling those observed in Lkb1 heterozygotes. Tumors were extremely well differentiated and histopathologically distinctive and exhibited alterations in AMP-dependent kinase signaling. Although Lkb1 has been implicated in the establishment of cell polarity, and loss of polarity defines most endometrial cancers, Lkb1-driven endometrial cancers paradoxically exhibit (given their highly invasive phenotype) normal cell polarity and apical differentiation. In human endometrial cancers, Lkb1 expression was inversely correlated with tumor grade and stage, arguing that Lkb1 inactivation or down-regulation also contributes to endometrial cancer progression in women. This study shows that Lkb1 plays an important role in the malignant transformation of endometrium and that Lkb1 loss promotes a highly invasive phenotype.

Retrospective cohort study of surgical staging for ovarian low malignant potential tumors.

OBJECTIVE: The purpose of this study was to determine the benefit of surgically staging ovarian low malignant potential tumors. STUDY DESIGN: This was a retrospective cohort study of all ovarian low malignant potential tumors that were diagnosed by frozen section or final pathologic review from 2003 to 2005. RESULTS: Twenty-two of 32 patients (69%) were staged surgically. Sixteen low malignant potential tumors were stage I by final pathologic review, and 4 tumors were upstaged to stage II-III disease. Two other patients had early invasive ovarian carcinoma, despite a frozen section that suggested low malignant potential; 1 patient received adjuvant chemotherapy. The tumors of 10 women (31%) were unstaged. Frozen section suspicion of low malignant potential (P = .003) and surgery by a gynecologic oncologist (P < .001) correlated with staging. Preoperative CA-125, intraoperative blood loss, and postoperative hospitalization were increased in patients with staged disease (each P < .05). Two women who underwent fertility-sparing surgery experienced a recurrence in the contralateral ovary. CONCLUSION: Surgical staging of ovarian low malignant potential tumors has limited value for most patients, unless invasive carcinoma is diagnosed by final pathologic review.