Lyuba Levine

Atypical glandular cells: New Bethesda terminology and management guidelines

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. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader will be able to outline the new Bethesda terminology and management guidelines and list the best devices for obtaining a Pap test.

Carbonic anhydrase IX and human papillomavirus as diagnostic biomarkers of cervical dysplasia/neoplasia in women with a cytologic diagnosis of atypical glandular cells: a Gynecologic Oncology Group study in United States.

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.

Primary small cell neuroendocrine carcinoma of the vagina: a clinicopathologic study.

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.

Use of BRCA Mutation Test in the U.S., 2004–2014

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 ClinformaticsTM 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 of 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.

Nutrition, Metabolism, and Integrative Approaches in Cancer Survivors

OBJECTIVES To review emerging issues about metabolic changes occurring in cancer survivors during and as a result of therapy, the role of nutrition, weight control, stress management, nutritional supplements, and other complementary diet therapies, methods of mitigating side effects of treatment affecting dietary intake, and to suggest future research directions. DATA SOURCES Literature review and professional clinical experience with oncology patients. CONCLUSION Enhancing cancer survivorship requires knowledge and application of nutritional science and integrative health care approaches. IMPLICATIONS FOR NURSING PRACTICE Reliable, personalized, team-generated nutritional advice must be provided to cancer patients and cancer survivors to reduce risk of recurrence, optimize energy balance, and improve quality of life.

Implications of tyrosine phosphoproteomics in cervical carcinogenesis

Background Worldwide 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. Methods Cervical 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. Results Annexin 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. Conclusion This 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.

Expression of gastrin-releasing peptide receptors in endometrial cancer

BACKGROUND The Bombesin (BBS)-related peptide, gastrin-releasing peptide, and its cognate receptor are ectopically expressed by many cancers, in which they regulate tumor proliferation and metastasis. But, their role in endometrial cancers is unknown. The purpose of this study was to determine whether endometrial cancer cell lines express functional BBS receptors and to determine whether they were coupled to the regulation of vascular endothelial growth factor (VEGF-A) expression. STUDY DESIGN Endometrial cancer cell lines (HEC-1A, KLE, and AN3CA) were cultured according to the recommendations of the American Tissue Culture Collection. Ishikawa cells were maintained in Dulbeccos modified Eagles medium plus 10% fetal bovine serum. Before BBS treatment, all cell lines were placed in serum-free, phenol-free media for 24 hours. BBS-stimulated increases in intracellular Ca(2+) ([Ca(2+)]i) were used to assess functional BBS receptor status. VEGF-A mRNA expression was determined by Northern blotting. RESULTS BBS (100 nM) stimulated an increase in [Ca(2+)]i in HEC-1A, Ishikawa, and KLE cells, indicating the presence of functional BBS receptors. This increase did not occur in AN3CA cells. BBS stimulated a time-dependent increase in VEGF-A mRNA expression in Ishikawa and KLE cells. Ishikawa cells exhibited a peak of VEGF-A mRNA expression between 8 and 12 hours with a partial decline by 24 hours. KLE cells showed a relatively small increase at 12 hours. In contrast, HEC-1A cells exhibited a high baseline level of VEGF-A mRNA expression and did not show a response to BBS. CONCLUSIONS These data demonstrate that endometrial cancer cell lines express functional BBS receptors. In Ishikawa, KLE, and HEC-1A cells, BBS receptors are coupled to the regulation of VEGF-A mRNA expression.

Carbonic anhydrase IX (CA-IX) and high-risk human papillomavirus (H-HPV) as diagnostic biomarkers of cervical dysplasia/neoplasia in Japanese women with a cytologic diagnosis of atypical glandular cells (AGC): A Gynecologic Oncology Group (GOG) Study

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.

WHAT COMPETENCIES SHOULD MEDICAL STUDENTS ATTAIN IN NUTRITIONAL MEDICINE

A sizable gap exists between the nutrition education offered in medical school and the dietary knowledge needed for patient care. Despite the centrality of nutrition to a healthy lifestyle and the pressing obesity epidemic, medical students receive limited training in nutrition. Often this instruction is focused on basic science and rare nutritional deficiency states rather than on the foundations of nutrition science needed to prepare physicians to address patient questions and nutritional needs. As a result, graduating medical students lack the knowledge and skills required to effectively promote behavior change in their patients. University instructors and graduating medical students agree that the approximately 25 contact hours of nutrition education provided to medical students is inadequate and even this low standard of hours is often not achieved. Furthermore, such instruction is focused on pathogenesis rather than the real world nutrition-related challenges of their patients, e.g., metabolic syndrome, cardiovascular disease, nutrition in cancer, obesity, and hospital malnutrition. Additionally, most medical schools do not provide nutrition education outside of the classroom, so most medical students do not get the opportunity to learn how to integrate nutrition knowledge into clinical practice. We propose an alternative to a narrowly focused basic science and nutritional training based on pathogenesis, rather by teaching nutrition as a key factor in salutogenesis, the generation of health and wellness. In parallel with this, teach students key skills to foster behavioral change.