Kathryn E. Sharpless

The Aspergillus nidulans sepA gene encodes an FH1/2 protein involved in cytokinesis and the maintenance of cellular polarity.

Cytokinesis (septation) in the fungus Aspergillus nidulans occurs through the formation of a transient actin ring at the incipient division site. Temperature‐sensitive mutations in the sepA gene prevent septation and cause defects in the maintenance of cellular polarity, without affecting growth and nuclear division. The sepA gene encodes a member of the growing family of FH1/2 proteins, which appear to have roles in morphogenesis and cytokinesis in organisms such as yeast and Drosophila. Results from temperature shift and immunofluorescence microscopy experiments strongly suggest that sepA function requires a preceding mitosis and that sepA acts prior to actin ring formation. Deletion mutants of sepA exhibit temperature‐sensitive growth and severe delays in septation at the permissive temperature, indicating that expression of another gene may compensate for the loss of sepA. Conidiophores formed by sepA mutants exhibit abnormal branching of the stalk and vesicle. These results suggest that sepA interacts with the actin cytoskeleton to promote formation of the actin ring during cytokinesis and that sepA is also required for maintenance of cellular polarity during hyphal growth and asexual morphogenesis.

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. LEVEL OF EVIDENCE: II-3

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. LEVEL OF EVIDENCE: III

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.

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 &khgr;2 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 &khgr;2 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.

Utilidad de la prueba del virus del papiloma humano en el manejo de las células glandulares atípicas en la citología

Objetivo. Determinar la utilidad de la prueba del virus del papiloma humano (VPH) para la enfermedad cervical asociada al VPH (EA‐VPH) y para el conjunto de la enfermedad (enfermedad cervical asociada a células glandulares atípicas [AGC]) en mujeres con AGC. Material y métodos. Se llevó a cabo una búsqueda bibliográfica correspondiente al periodo comprendido entre enero de 1993 y septiembre de 2007, utilizando diversos términos relacionados con las AGC, junto con términos de Medical Subject Heading (MeSH) “HPV” ampliado. Se utilizaron los resultados de 7 estudios para calcular las tasas de enfermedad según el estado del VPH. Resultados. La tasa de enfermedad cervical asociada a AGC para 661 casos de AGC con pruebas de VPH simultáneas fue del 23,3%. La tasa de EA‐VPH fue mayor en las mujeres con VPH positivos, en comparación con las que tenían un VPH negativo (53% frente a 3%, respectivamente). El estado de positividad para el virus del papiloma humano, en comparación con el de negatividad, predijo una mayor proporción de lesiones de neoplasia intraepitelial cervical 2/3 (odds ratio = 39,6, IC del 95% = 17,9‐87,4, p < 0,001). La tasa de cánceres no asociados a VPH fue significativamente superior en las pacientes negativas, en comparación con las positivas, para el VPH (4% frente a 0,4%; p = 0,016). La prueba del virus del papiloma humano tuvo una sensibilidad global del 90%, una especificidad del 79%, un valor predictivo positivo del 53% y un valor predictivo negativo del 97% para los casos de EA‐VPH. Las células glandulares atípicas con presencia simultánea de células escamosas atípicas (ASC) o de lesión intraepitelial escamosa (SIL) (ASC/SIL) presentaron tasas de enfermedad superiores a las de las AGC solas. El valor predictivo positivo de la prueba de VPH para las AGC con presencia simultánea de ASC/SIL fue superior al de las AGC solas. Conclusiones. En todas las mujeres con AGC debe realizarse un examen inicial detallado, sea cual sea el estado del VPH. La presencia de VPH identifica a un grupo de mujeres con mayor riesgo de enfermedad cervical que deben ser objeto de un seguimiento estricto. Las mujeres positivas para el virus del papiloma humano con AGC y presencia simultánea de ASC/SIL tienen un riesgo aún mayor. Si, tras un examen inicial completo, las mujeres con AGC sin otra especificación y con un VPH positivo no tienen ninguna causa identificable, puede considerarse una conización cervical. ▪