Introduction BRCA mutation testing has been used for screening women at high risk of breast and ovarian cancer and for selecting the best treatment for those with breast cancer. To optimize the infrastructure and medical resources allocation for genetic testing, it is important to understand the use of BRCA mutation testing in the U.S. health system. Methods This retrospective cohort study included 53,254 adult women with insurance claims for BRCA mutation testing between 2004 and 2014 from Clinformatics™ Data Mart Database. Data analysis was performed in 2016. This study assessed trends in the use of BRCA mutation testing in women with previously diagnosed breast or ovarian cancer and those without (unaffected women). Results Between 2004 and 2014, of those receiving BRCA testing, the proportion of BRCA tests performed in unaffected women increased significantly (p<0.001), from 24.3% in 2004 to 61.5% in 2014. An increase in the proportion of BRCA tests used in unaffected women was found in each characteristic subgroup. In 2014, most subgroups had a proportion surpassing 50%, except for those aged 51–65 years and those without a family history of breast cancer. There was a much lower proportion those aged 20–40 years among tested women with previously diagnosed breast or ovarian cancer than in unaffected women (17.6% vs 41.7%, p<0.001). Conclusions During the past decade, the role of BRCA testing has gradually shifted from being used primarily in cancer patients to being used in unaffected women in the U.S.

Although Pap tests have enabled early detection of premalignant lesions, the introduction of new collecting devices has significantly improved the detection of lesions hidden in the endocervical canal, such as adenocarcinoma in situ (AIS). The term "atypical glandular cells of undetermined significance" (AGUS) was introduced at the 1988 Bethesda Conference and defined as morphologic changes in glandular cells beyond those that are suggestive of the benign reactive process, but insufficient for the diagnosis of adenocarcinoma in situ (AIS). In the new 2001 Bethesda System, the term has been eliminated and replaced with the term "atypical glandular cells" (AGC), with the following subclassifications: not otherwise specified (NOS), favor neoplasia, endocervical AIS, and adenocarcinoma. The risks of premalignant or malignant disease associated with the AGC favor neoplasia category are substantially higher than in the AGC NOS category (96% vs. 9-41%, respectively). Patients diagnosed with AGC NOS or AGC favor neoplasia will require colposcopy, endocervical sampling, and, for patients over 35 years of age, endometrial biopsy. If all of these tests are negative, the Pap test should be repeated in 4-6 month intervals until 4 consecutive normal tests are obtained. Positive results in one of the tests will require management according to ASCCP guidelines. The AGC favor neoplasia diagnosis also requires cervical conization and/or other testing, as the incidence of premalignant or malignant lesions in patients with this diagnosis is high. The role of HPV testing in this setting is unknown at this time.

BackgroundStandard-of-care (SOC) cancer treatments are primarily aimed at reducing size and progression of a tumor. There is a need for successful supplemental anabolic therapies to combat cancer cachexia in addition to these SOC treatment modalities. Anabolic interventions, including testosterone and amino acid supplements, may be beneficial in reducing and/or reversing muscle wasting in these patient populations.MethodsA 48-year-old Caucasian female with recurrent cervical cancer was scheduled to receive three 21-day cycles of cisplatin and topetecan chemotherapy. She qualified, consented, and enrolled into a blinded interventional pilot study where she received daily whey protein (10 g, three times per day with meals) and a weekly injection of testosterone enanthate (100 mg intramuscular) before and during the SOC chemotherapy treatment period. Body composition, serum inflammatory markers, mixed muscle protein synthesis and breakdown rates, physical function, fatigue, and quality of life were assessed before and after the intervention period.ResultsBody composition, as assessed by an increase in body weight and lean body mass and reduction in fat mass; physical function; fatigue; and quality of life each improved across the entire intervention period despite general increases in inflammatory markers and no improvements in muscle protein turnover towards the end of the intervention.ConclusionsConcomitant treatment of oral amino acids and testosterone may be a viable therapeutic option for fighting cachexia and improving body composition and quality of life during chemotherapeutic treatment of recurrent cervical cancer. These positive outcomes may be attainable over time despite overall poor inflammatory status.

High‐risk human papillomavirus (H‐HPV) infection is strongly linked to cervical neoplasia, but its role in detecting glandular lesions (GLs) is unclear. In the cervix, carbonic anhydrase IX (CA‐IX) is expressed in cervical neoplasia, but rarely in the benign cervix. The diagnostic utility of these biomarkers was evaluated in women with a cytologic diagnosis of atypical glandular cells (AGC). H‐HPV was detected using hybrid capture 2 (HC2) in liquid‐based cytology, and CA‐IX immunoreactivity was studied on conventional Pap smears. Of 403 patients, 111 (28%) were positive for significant cervical lesions (SCLs) including CIN2, CIN3, adenocarcinoma in situ or invasive carcinoma. CA‐IX testing alone (n = 403) had a sensitivity of 75, 95 or 65% for SCLs, significant GLs or squamous lesions (SLs), respectively, with a specificity of 88% and a false negative rate (FNR defined as 1 minus negative predictive value) of 10%. Testing for H‐HPV (n = 122) had a sensitivity of 97, 100 or 96% for SCLs, GLs or SLs, respectively, with a specificity of 87% and a FNR of 1%. The combination of CA‐IX and H‐HPV testing (n = 122), collectively, had the same sensitivity, specificity and FNR for SCLs, GLs or SLs as H‐HPV testing alone. The conclusions of our study are that both H‐HPV and CA‐IX testing are useful diagnostic markers for GLs. However, H‐HPV testing is a better diagnostic marker for SLs. The combination of CA‐IX with H‐HPV testing does not improve the diagnostic accuracy for cervical neoplasia in women with AGC diagnosis over that of H‐HPV testing alone. © 2009 UICC

Context.—Primary small cell neuroendocrine carcinoma of the vagina is extremely rare, and its clinical behavior is aggressive. To our knowledge, 22 patients with this tumor have been reported in the English literature to date. Objective.—To investigate 3 patients with this tumor clinically and pathologically. Design.—The pathology database at the University of Texas Medical Branch at Galveston was searched, and 3 cases of primary small cell neuroendocrine carcinoma of the vagina were found. The histologic, immunohistochemical, and ultrastructural profiles of the tumors were investigated. The medical charts of the patients were reviewed, and the patients were followed up. Patients.—Women with the diagnosis of primary small cell neuroendocrine carcinoma of vagina. Results.—All 3 patients presented with advanced disease, and 2 patients died within 4 months of the initial diagnosis. One 38-year-old patient was newly diagnosed, and her clinical outcome had not yet been determined. The histologic features of all 3 tumors were similar to those of their pulmonary counterpart. All cases were positive for cytokeratin, chromogranin A, and synaptophysin. The expression pattern of thyroid transcription factor 1 was examined in all 3 patients, of whom 2 were negative and 1 was positive with negative clinical and radiologic thyroid or pulmonary findings. Ultrastructural evaluation showed scattered intracytoplasmic electron-dense neurosecretory granules. Conclusion.—Primary small cell neuroendocrine carcinoma of the vagina has histologic, immunohistochemical, and ultrastructural features similar to those of its pulmonary counterpart. Because thyroid transcription factor 1 can be positive, it should not be used to differentiate primary from metastatic disease. The current therapies have usually resulted in poor outcomes, and new therapeutic modalities should be explored.

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BackgroundWorldwide cervical cancer remains a leading cause of mortality from gynecologic malignancies. The link between cervical cancer and persistent infection with HPV has been established. At a molecular level little is known about the transition from the precancerous state to invasive cancer. To elucidate this process, cervical biopsies from human specimens were obtained from precancerous state to stage III disease.MethodsCervical biopsies were obtained from patients with a diagnosis of cervical cancer undergoing definitive surgery or staging operation. Biopsies were obtained from patients with precancerous lesions at the time of their excisional procedure. Control samples were obtained from patients undergoing hysterectomy for benign conditions such as fibroids. Samples were subjected to proteomic profiling using two dimensional gel electrophoresis with subsequent trypsin digestion followed by MALDI-TOF protein identification. Candidate proteins were then further studied using western blotting, immunoprecipitation and immunohistochemistry.ResultsAnnexin A1 and DNA-PKcs were found to be differentially expressed. Phosphorylated annexin A1 was up regulated in diseased states in comparison to control and its level was strongly detected in the serum of cervical cancer patients compared to controls. DNA-PKcs was noted to be hyperphosphorylated and fragmented in cancer when compared to controls. By immunohistochemistry annexin A1 was noted in the vascular environment in cancer and certain precancerous samples.ConclusionThis study suggests a probable role for protein tyrosine phosphorylation in cervical carcinogenesis. Annexin A1 and DNA-PK cs may have synergistic effects with HPV infection. Precancerous lesions that may progress to cervical cancer may be differentiated from lesions that will not base on similar immunohistochemical profile to invasive squamous cell carcinoma.

Background:High-risk human papillomavirus (H-HPV) infection is linked to cervical neoplasia but its role in detecting cervical glandular lesions (GLs) is unclear. Carbonic anhydrase IX (CA-IX) is a hypoxic biomarker that is highly expressed in neoplastic cervical GLs. The diagnostic utility of these biomarkers was evaluated by the Gynecologic Oncology Group in Japanese women with a cytological diagnosis of atypical glandular cells.Methods:Immunostaining was used to detect CA-IX in a conventional Pap smear. Immunoreactivity of CA-IX was interpreted by a panel of pathologists blinded to the histological diagnosis. Polymerase chain reaction was used to detect H-HPV in a liquid-based cytology specimen.Results:Significant cervical lesions (SCLs), defined as cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ or invasive carcinoma, were observed in 37/88 (42%) of women. CA-IX testing alone (n=88) had a sensitivity of 89, 100 or 73% for SCLs, GLs or significant squamous lesions (SLs), respectively, with a false negative rate (FNR) of 14%. Testing for H-HPV (n=84) had a sensitivity of 65, 53 or 80% for SCLs, GLs or SLs, respectively, with a FNR of 22%. The combination of CA-IX and H-HPV testing had a sensitivity of 97, 100 or 93% for SCLs, GLs or SLs, respectively, with a FNR of 5%. Among eight H-HPV-negative GLs, six (75%) had a diagnosis of lobular endocervical glandular hyperplasia (LEGH).Conclusion:The combination of CA-IX and HPV testing improved the diagnostic accuracy. The low rate of H-HPV positivity in the GLs was associated with coexisting LEGH independent of H-HPV.