ASCCP Committee Opinion: Adjuvant Human Papillomavirus Vaccine for Patients Undergoing Treatment for Cervical Intraepithelial Neoplasia.

OBJECTIVES: Individuals treated for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) are at long-term risk of persistent or recurrent disease despite treatment. This committee opinion aims to summarize and provide evidence-based recommendations for adjuvant human papillomavirus (HPV) vaccination based on available, published literature. METHODS: A task force from the ASCCP Practice Committee reviewed current Centers for Disease Control and Prevention (CDC) guidelines and previously published literature about the role of adjuvant HPV vaccination in previously unvaccinated individuals undergoing treatment for CIN2+ and other HPV-related diseases. RESULTS: Current CDC guidelines recommend routine or catch-up HPV vaccination for individuals aged 9 to 26 years, and shared decision making regarding vaccination for individuals aged 27 to 45 years. Multiple published studies suggest a possible benefit for adjuvant HPV vaccination in previously unvaccinated individuals undergoing treatment for CIN2+. CONCLUSIONS: The American Society for Colposcopy and Cervical Pathology recommends adherence to current CDC recommendations for vaccination of individuals aged 9 to 26 years and consideration of the possible benefit of adjuvant HPV vaccination during shared decision making for previously unvaccinated individuals aged 27 to 45 years who are undergoing treatment for CIN2+.

Severe hemorrhage due to acquired uterine arteriovenous malformation/fistula following first-trimester aspiration abortion: A case report.

Uterine arteriovenous malformation/arteriovenous fistula is a rare, but potentially life-threatening, cause of severe hemorrhage. A case of uterine arteriovenous malformation/fistula causing severe hemorrhage following a first-trimester aspiration abortion procedure in a patient with a history of prior cesarean sections is presented. In this case, the patient was promptly diagnosed and effectively treated with uterine artery embolization. Consideration of uterine arteriovenous malformation/fistula in the differential diagnosis of severe hemorrhage following first-trimester aspiration abortion, especially in women with risk factors, can lead to timely recognition and appropriate treatment.

Atypical Glandular Cells of Endometrial Origin and the Risk of Endometrial Cancer.

OBJECTIVES: To assess the risk of endometrial cancer (EC) associated with atypical glandular cells of endometrial origin (AGC-EM) in 2 age groups (age younger than 51 vs 51 years or older). METHODS: A retrospective case series was assembled identifying AGC from a pathology database between January 1, 2005 and January 1, 2009. Demographics, cervical cytology results, and final diagnoses (including clinically significant diseases and cancers) were recorded from the initial AGC diagnosis until August 30, 2011. Data were analyzed using the χ test to compare rates of disease between age groups. RESULTS: Among the 444 patients with AGC, 41% (183/444) had AGC-EM. Women younger than 51 years, compared to those 51 years or older, had significantly lower rates of AGC-EM (35% [105/296] vs 53% [78/148]; p < .001; odds ratio, 0.49; 95% confidence interval, 0.33-0.74). The rate of EC was significantly lower in those younger than 51 years, compared to those aged 51 or older (5% [8/158] vs 19% [18/95]; p < .001; odds ratio, 0.23; 95% confidence interval, 0.09-0.55) in women who underwent endometrial biopsy. In women younger than 51 years who underwent an endometrial biopsy, the rate of EC had a stepwise increase across 3 subclasses of AGC (from AGC of endocervical origin [AGC-EC] to AGC not otherwise specified to AGC-EM) (p = .04). CONCLUSIONS: Women aged 51 years or older who have AGC are more likely to have AGC-EM and EC than women younger than 51 years. In women younger than age 51, AGC-EM is the subclass most associated with EC while compared to 2 other subclasses (AGC not otherwise specified and AGC-EC).

Management of "Atypical Endocervical Cells" Compared to "Atypical Glandular Cells".

OBJECTIVE: To assess adherence to management guidelines based on the terminology used to describe atypical glandular cells (AGC) on cytology reports. MATERIALS AND METHODS: We analyzed AGC pathology reports from Hartford Hospital, 2004-2007, and identified cases of AGC with the terminology atypical glandular cells or atypical endocervical cells (AEC). We calculated rates of clinical evaluations based on the terminology used to describe the AGC. Statistical analysis was performed using the χ test. RESULTS: Seventy-eight reports contained the terminology AEC and 97 reports contained the terminology AGC. The rate of histologic sampling in women with AEC was lower than in women with AGC (52.6% vs 83.5%; p < .01). Similarly, the rate of comprehensive evaluations was lower (33.3% vs 71.1%; p < .01). Fewer endocervical curettages (47.4% vs 77.3%; p < .01) and fewer endometrial biopsies in women 35 years or older were performed (26.9% vs 69.1%; p < .01) in women with AEC than in women with AGC. CONCLUSIONS: Women with AGC reports containing the term AEC were managed less optimally than those with AGC. These results suggest that the terminology used to describe the finding of atypical glandular cells may influence the clinical evaluation. Clinicians may not recognize AEC as AGCs. Ours results suggest that the terminology atypical endocervical cells should be avoided or accompanied by the terminology atypical glandular cells.

Adherence to practice guidelines for atypical glandular cells on cervical cytology.

BACKGROUND: Atypical glandular cells (AGC) on cervical cytology are high-risk, requiring an extensive evaluation. Compliance with practice guidelines for AGC, however, has been low. Some AGC cytology reports contain cytopathologist recommendations for evaluation. This study determines whether evaluation rates for AGC have improved over time, and whether cytopathologists' recommendations correlate with the types of evaluation women receive. METHODS: Evaluation rates from 284 women with AGC (2004-2007) were compared with findings from 1998-2001. Rates of evaluations were compared based on cytology report recommendations. RESULTS: A total of 76.1% of the AGC cases had histologic sampling, and 58.8% had a comprehensive evaluation. These rates are higher than those from 1998-2001 (63.5% and 35.8%, respectively; P<.01). Rates of evaluations of women with AGC "favor neoplasia" did not increase between the 2 time periods. Between 2004-2005 and 2006-2007, rates of comprehensive initial evaluations and endometrial sampling in women ≥35 years of age did not increase. Of the AGC reports that did contain cytopathologist recommendations, 28% were consistent with practice guidelines, 26% recommended an incomplete histologic evaluation, and 46% recommended repeat cytology. Women whose AGC report recommended a comprehensive evaluation or any histologic evaluation were more likely to have a comprehensive work-up (79%) than those whose reports did not contain recommendations (55%, P <0.01) or recommended repeat cytology (51%, P<0.02). CONCLUSIONS: Adherence to practice guidelines for the evaluation of women with AGC has improved but continues to be suboptimal. Our findings suggest that continuing education and including practice guidelines on AGC cytology reports may improve compliance.

Atypical glandular cells on cervical cytology and breast disease: what is the association?

OBJECTIVE: To determine whether metastatic mammary carcinoma can be detected on cervical cytology in patients with atypical glandular cells (AGCs). METHODS: This blinded study of AGC cases with a matched control group was approved by Hartford Hospital institutional review board. Between January 2002 and November 2008, inclusive, all Pap tests in our database with AGC were identified. The AGC cases from patients with breast disease, compared with the control group of AGC patients without breast disease, were reanalyzed independently by 2 pathologists. RESULTS: Among the 40 women who had an AGC Pap test with breast disease, 21 cases were available for review (16 with invasive and 5 with in situ breast lesions). Seventeen cases of AGC in patients without breast disease served as the control group. The 2 pathologists agreed with the original Pap finding (AGC) in 84.2% to 89.5% of cases. There were no cases, either among those with breast disease or those without, where cells consistent with breast disease were seen, nor were "tamoxifen cells" identified, on Pap testing. CONCLUSIONS: Studies have found that an association exists between patients with AGCs on cervical cytology and extrauterine malignancies, including breast disease. The results of this analysis would suggest that, at least for breast disease, the higher association of cancer or precancerous lesions in those with AGC is not related to the direct extension of disease or metastasis. Further research will be needed to help delineate the potential etiology of this association.

The utility of human papillomavirus testing in the management of atypical glandular cells on cytology.

OBJECTIVE: To determine the value of human papillomavirus (HPV) testing for HPV-associated cervical disease (HPV-AD) and overall disease (atypical glandular cell [AGC]-associated cervical disease) in women with AGCs. MATERIALS AND METHODS: A literature search was conducted from January 1993 through September 2007 using various AGC-related terms with the exploded Medical Subject Heading (MeSH) term "HPV." Findings from 7 studies were used to calculate disease rates according to HPV status. RESULTS: The rate of AGC-associated cervical disease for 661 cases of AGC with concurrent HPV testing was 23.3%. The rate of HPV-AD was higher in HPV-positive, versus negative, cases (53% vs 3%, respectively). Human papillomavirus-positive, versus negative, status predicted a higher likelihood of a cervical intraepithelial neoplasia 2/3 lesion (odds ratio = 39.6, 95% CI = 17.9-87.4, p <.001). The rate of HPV-nonassociated cancers was significantly higher in patients who were negative, versus positive, for HPV (4% vs 0.4%; p =.016). Human papillomavirus testing had an overall 90% sensitivity, 79% specificity, 53% positive predictive value, and 97% negative predictive value for cases of HPV-AD. Atypical glandular cell with concurrent atypical squamous cell (ASC) or squamous intraepithelial lesion (SIL) (ASC/SIL) had higher rates of disease than AGC alone. The positive predictive value of HPV testing for AGC with concurrent ASC/SIL was higher than that for AGC alone. CONCLUSIONS: All women with AGC should undergo a comprehensive initial examination regardless of HPV status. The presence of HPV identifies a group of women at higher risk for cervical disease who should be followed closely. Women positive for human papillomavirus with AGC and concurrent ASC/SIL are at even higher risk. If, after a comprehensive initial examination, women with AGC not-otherwise-specified and positive HPV have no identifiable disease, a cervical conization may be considered.

Use of human papillomavirus testing in the management of atypical glandular cells.

OBJECTIVE: To analyze the role of human papillomavirus (HPV) testing in the management of women with atypical glandular cells (AGCs). MATERIALS AND METHODS: After institutional review board approval, cases of AGC with concurrent HPV testing were identified from the pathology database at Hartford Hospital from January 2000 to September 2006, inclusive. Atypical glandular cell-associated disease included cervical intraepithelial neoplasia 2 (CIN 2) or anything of greater pathologic importance on histology. Human papillomavirus-associated disease included CIN 2-3, glandular atypia, adenocarcinoma in situ, or any cervical malignancy. RESULTS: Two hundred fourteen cases of AGC with concurrent HPV testing were evaluated, including 27 cases of AGC with concurrent atypical squamous cells, low-grade squamous intraepithelial lesions, or high-grade squamous intraepithelial lesions. The rate of disease was 20.6%, with a 7.0% prevalence of cancer. Among the 214 cases of AGC, 30.4% tested positive for HPV. The rate of HPV-associated disease among cases testing positive for HPV was 40.0% compared with 4.0% among HPV-negative cases. The sensitivity of HPV testing for HPV-associated disease was 81.3%. Women positive for human papillomavirus were less likely to have endometrial or extrauterine disease (1.5%) than HPV-negative women (7.4%). CONCLUSIONS: All women with AGC on cervical cytology require colposcopy and endocervical curettage regardless of HPV status. Women positive for human papillomavirus are at higher risk than HPV-negative women for cervical disease and should be evaluated and followed up closely. Women at risk for endometrial or extrauterine malignancies should undergo appropriate evaluation regardless of HPV status.

Dysplasia associated with atypical glandular cells on cervical cytology.

OBJECTIVES: To estimate the rates of and identify risk factors for disease in women with atypical glandular cells of undetermined significance (AGUS). METHODS: From 1998-2001, 477 Pap tests at Hartford Hospital were classified as AGUS and met the inclusion criteria of this study. Findings were evaluated for 2 years from the initial test. Disease was defined as histology results with a finding of high-grade squamous intraepithelial lesion or greater. RESULTS: Disease was diagnosed in 9% of the women, including malignancy in 3%. Women with malignant-appearing AGUS Pap tests had a higher rate of disease (29%) than women with benign-appearing (5%, P < .01) and unspecified AGUS Pap tests (13%, P < .03). Malignancies were associated with all subclassifications of AGUS Pap tests. Women aged less than 35 years were more likely to have disease than women aged 35 years or older (P < .02). Most women aged younger than 35 years had a squamous abnormality, whereas women aged 35 years or older had a greater diversity of squamous and glandular lesions and accounted for all cases of endometrial cancer, adenocarcinoma in situ, and cervical adenocarcinoma. Women with persistent AGUS Pap tests had a 31% rate of disease. The rate of disease among women with AGUS Pap tests collected by liquid-based cytology was 11%, compared with 6% among samples collected by the conventional method. CONCLUSION: These data suggest that women with atypical glandular cells are at substantial risk for dysplasia and malignancy. The rate of disease varies with the method of Pap test collection, age, presence of persistent AGUS Pap tests, and AGUS subclassification.

Lack of adherence to practice guidelines for women with atypical glandular cells on cervical cytology.

OBJECTIVE: We sought to estimate the rates and types of evaluation in women with atypical glandular cells of undetermined significance (AGC-US) on cervical cytology and to assess these findings on the basis of published management guidelines. METHODS: The rates of histologic sampling, comprehensive initial evaluations, and secondary evaluations were assessed in 477 women with an AGC-US Pap test from 1998 to 2001. A comprehensive evaluation was defined as a colposcopy and an endocervical curettage with or without a cervical biopsy. For women aged 35 or older, a comprehensive evaluation also included an endometrial biopsy. A secondary evaluation consisted of a diagnostic cone biopsy. RESULTS: Sixty-four percent of women with an AGC-US Pap test had histologic sampling; 36% were followed by repeat Pap test only. Thirty-six percent of women with an AGC-US Pap test had a comprehensive evaluation. Women with an AGC-US Pap test that was subclassified as malignant-appearing had higher rates of histologic and comprehensive evaluations than women with a benign-appearing or unspecified AGC-US Pap test (P < .01). Twenty-eight percent of women aged 35 or older had comprehensive evaluations compared with 57% of women younger than the age of 35 (P < .01). Secondary evaluations were performed in 8% of women with persistent AGC-US Pap tests and 2% of women with malignant-appearing AGC-US Pap tests after negative initial histologic evaluations. Twelve of the 42 cases of disease (29%) were diagnosed more than 1 year from the initial AGC-US Pap test. CONCLUSION: On the basis of accepted management guidelines, these data suggest that women with AGC-US Pap tests are undermanaged in both their initial and secondary evaluations.

MesA, a novel fungal protein required for the stabilization of polarity axes in Aspergillus nidulans.

The Aspergillus nidulans proteome possesses a single formin, SepA, which is required for actin ring formation at septation sites and also plays a role in polarized morphogenesis. Previous observations imply that complex regulatory mechanisms control the function of SepA and ensure its correct localization within hyphal tip cells. To characterize these mechanisms, we undertook a screen for mutations that enhance sepA defects. Of the mutants recovered, mesA1 causes the most dramatic defect in polarity establishment when SepA function is compromised. In a wild-type background, mesA1 mutants undergo aberrant hyphal morphogenesis, whereas septum formation remains unaffected. Molecular characterization revealed that MesA is a novel fungal protein that contains predicted transmembrane domains and localizes to hyphal tips. We show that MesA promotes the localized assembly of actin cables at polarization sites by facilitating the stable recruitment of SepA. We also provide evidence that MesA may regulate the formation or distribution of sterol-rich membrane domains. Our results suggest that these domains may be part of novel mechanism that directs SepA to hyphal tips.

Functional characterization and localization of the Aspergillus nidulans formin SEPA.

Formins are a family of multidomain scaffold proteins involved in actin-dependent morphogenetic events. In Aspergillus nidulans, the formin SEPA participates in two actin-mediated processes, septum formation and polarized growth. In this study, we use a new null mutant to demonstrate that SEPA is required for the formation of actin rings at septation sites. In addition, we find that a functional SEPA::GFP fusion protein localizes simultaneously to septation sites and hyphal tips, and that SEPA colocalizes with actin at each site. Using live imaging, we show that SEPA localization at septation sites and hyphal tips is dynamic. Notably, at septation sites, SEPA forms a ring that constricts as the septum is deposited. Moreover, we demonstrate that actin filaments are required to maintain the proper localization pattern of SEPA, and that the amino-terminal half of SEPA is sufficient for localization at septation sites and hyphal tips. In contrast, only localization at septation sites is affected by loss of the sepH gene product. We propose that specific morphological cues activate common molecular pathways to direct SEPA localization to the appropriate morphogenetic site.