Pilot Study of Markers for High-grade Anal Dysplasia in a Southern Cohort From the Women's Interagency Human Immunodeficiency Virus Study.

BACKGROUND: Anal cancer rates have increased, particularly in human immunodeficiency virus (HIV)-infected (HIV+) women. We assessed factors associated with anal precancer in HIV+ and at-risk HIV-negative women from the Atlanta Women's Interagency HIV Study cohort. METHODS: All participants underwent high-resolution anoscopy and anal cytology and had anal and cervical samples collected. Specimens were tested for 37 human papillomavirus (HPV) types and for FAM19A4 and microRNA124-2 promoter methylation. Binary logistic regression and multivariate analysis were conducted with histologic anal high-grade squamous intraepithelial lesion (A-HSIL) as the dependent variable. RESULTS: Seventy-five women were enrolled: 52 (69%) were HIV+ with three-fourths having undetectable viral load; 64 (86%) were black; mean age was 49 ± 8 years. Forty-nine (65%) anal cytology samples were abnormal, and 38 (51%) of anal samples were positive for at least 1 of 13 high-risk HPV (hrHPV) types. Thirteen (18%) anal biopsies identified A-HSIL. Hypermethylation of FAM19A4 and/or microRNA124-2 was found in 69 (95%) anal samples and 19 (26%) cervical samples. In multivariate analyses, the odds of having A-HSIL were >6 times higher in women with anal hrHPV (adjusted odds ratio [aOR], 6.08 [95% confidence interval {CI}, 1.27-29.18], P = .02) and with positive cervical methylation (aOR, 6.49 [95% CI, 1.66-25.35], P = .007), but not significantly higher in women with positive anal methylation. CONCLUSIONS: Anal hrHPV and promoter hypermethylation in the cervix show promise as biomarkers for anal cancer screening in HIV+ and at-risk HIV-negative women. Greater understanding of gene silencing by promoter hypermethylation in anal carcinogenesis is needed.

Diagnosing Anal Squamous Intraepithelial Lesions With and Without p16: An Interobserver Variability Study.

OBJECTIVE: Morphologic diagnosis and grading of anal squamous intraepithelial lesions (ASILs) are challenging. In this study, we investigated interobserver variability and p16 utility in accurately grading anal SIL. MATERIALS AND METHODS: Six pathologists evaluated the degree of SIL on hematoxylin and eosin slides from 146 anal biopsies, followed by the review of both p16 and hematoxylin and eosin slides in cases where p16 was previously performed. κ was calculated in the following 4 ways: (A) 4-tiered diagnosis (negative for SIL [NSIL], anal intraepithelial neoplasia [AIN 1, AIN 2, AIN 3]); (B) 3-tiered diagnosis (NSIL and AIN 1 [pooled], AIN 2, AIN 3); (A) 3-tiered diagnosis (NSIL, low-grade SIL, high-grade SIL [HSIL]); and (D) 2-tiered diagnosis (no HSIL, HSIL). RESULTS: There is only moderate agreement with a 4-tiered diagnosis with or without p16 (κ = 0.48-0.57). There is substantial agreement when AIN 2 and AIN 3 are pooled as HSIL in cases with or without p16 review (κ = 0.71-0.78). There is almost perfect agreement with a 2-tiered diagnosis of negative for HSIL and HSIL both in cases where p16 was used and where p16 was not required, with the best agreement for a 2-tiered diagnosis with concurrent p16 review. CONCLUSIONS: This study highlights the importance of a judicious use of p16 for diagnosis. When there is no need for p16 by the Lower Anogenital Squamous Terminology guidelines, interobserver agreement was substantial to almost perfect with a 2-tiered diagnosis. However, when its use is indicated but it is not performed or reviewed, the agreement is much lower even with a 2-tiered diagnosis. Rational use of p16 will ensure diagnostic accuracy and the best possible patient care.

Do High Rates of Atypical Glandular Cells Correlate With Higher Incidence of Disease in a Large Safety Net Hospital.

OBJECTIVE: The aim of the study was to describe the incidence and correlates of atypical glandular cell (AGC) Pap tests in a low socioeconomic status, underserved population. MATERIALS AND METHODS: Medical records of patients with AGC Pap tests at a single institution were reviewed from January 2013 to August 2019. Baseline characteristics were extracted including age, body mass index, birth control, abnormal uterine bleeding, and human papillomavirus (HPV). All colposcopy and endometrial biopsies were classified into negative/low-risk (polyps, tubular metaplasia, microglandular hyperplasia, cervical intraepithelial neoplasia 1) and high-risk (HR) lesions (cervical intraepithelial neoplasia 2/3, adenocarcinoma in situ, endometrial hyperplasia, cervical cancer, endometrial cancer). Logistic regression identified significant associations. Sixty-eight randomly selected AGC cytology slides from the cohort and 32 non-AGC slides outside the cohort were blindly reviewed by 6 pathologists. Fleiss κ interrater agreement was assessed. RESULTS: Seven hundred forty patients with AGC Pap tests were identified (0.8% of all Pap tests performed during this time). After excluding for incomplete data, 478 patients were included. Sixty-three patients had HR lesions (13.3%). Patients with HR lesions had increased odds of abnormal uterine bleeding (odds ratio = 4.32, p < .001) and HPV positivity (odds ratio = 10.89, p < .001) when compared with patients with low-risk lesions. The κ agreement was 0.21 for all cases and 0.18 for AGC alone. CONCLUSIONS: This population falls within the national averages for AGC Pap tests. There was an increased risk of HR lesions in patients with abnormal uterine bleeding and HPV positivity. The rate of HR lesions among AGC Pap tests was at the lower end of values in the literature. After blinded pathologist review, interobserver κ agreement was low for AGC Pap tests.

Adrenal gland fine needle aspiration: a multi-institutional analysis of 139 cases.

INTRODUCTION: Adrenal gland lesions span a range of entities from benign and malignant primary neoplasms to metastatic tumors. Fine-needle aspiration (FNA) provides a minimally invasive diagnostic tool to stage patients with known malignancy and procure material for molecular testing. This study characterizes the clinicopathologic associations of patients with adrenal gland FNA from 2 large hospitals. MATERIALS AND METHODS: FNAs were identified by query of electronic medical record from 2002-2019. Clinical and pathological information was collated and correlated with corresponding surgical diagnosis when available. RESULTS: Of 139 cases, the majority (n = 127, 91%) were adequate computed tomography-guided FNAs and included the following diagnoses: positive for malignancy (n = 77, 55%), negative for malignancy (n = 32, 23%), neoplastic cells present (n = 16, 12%), nondiagnostic (n = 12, 9%), atypical (n = 1, 1%), and suspicious for carcinoma (n = 1, 1%). The majority (94%, n = 72 of 77) of malignancies were metastatic tumors, most frequently carcinoma (n = 53 of 72, 74%), followed by melanoma (n = 11 of 72, 15%), lymphoma (n = 4 of 72, 6%), and sarcoma (n = 4 of 72, 6%). Metastatic carcinomas included lung (n = 21 of 72, 29%), genitourinary (n = 12 of 72, 17%), and hepatobiliary or gastrointestinal tract (n = 11 of 72, 15%) primaries. Primary adrenal neoplasms (n = 23) included adenomas (n = 11 of 23, 48%), pheochromocytomas (n = 4 of 23, 17%), and myelolipomas (n = 3 of 23, 13%). Thirty-two patients with metastases died of disease after median follow-up of 8 months. CONCLUSIONS: High specimen adequacy (n = 127, 91%) and low indeterminate rates (n = 2, 2%) are achieved with adrenal FNA. Most aspirated lesions represent metastases from primary lung carcinomas, but other primary sites including those below the diaphragm are part of the diagnostic differential. Adrenal metastasis was associated with a poor prognosis, with median survival of 8 months.

Löwenstein-Buschke: Clinicopathologic Analysis of 78 Cases of Large and Giant Condyloma Acuminata of the Anus.

OBJECTIVE: The nature and clinicopathologic associations of Löwenstein-Buschke disease are unclear. MATERIALS AND METHODS: 78 anal condylomatous lesions (≥2 cm) were analyzed. Cases were classified based on size as "medium-large"(2-5 cm, n=59), "large" (5-10 cm, n=13) and "giant" ( > 10 cm, n=6). RESULTS: Patients were predominantly males (male/female=70/8). The mean age was 38 years (range:20-66). Two distinct lining types were recognized: 1) Epidermal type, typically lacking overt koilocytotic change, with associated invasive carcinoma in 8%; 2) Mucosal type, often manifesting koilocytotic change, with associated invasive carcinoma in 21%. Three types of high-grade dysplasia were discerned: 1) Basaloid, 8/9 showing high-grade dysplasia/carcinoma in-situ but non-invasive lesions; 2) Keratinizing, innocuous-appearing, but 5/6 was associated with invasion; 3) Giant cell, showing scattered individual bizarre cells, with 3/5 showing invasive carcinoma. Overall, invasion was found in 14% of the cases. The bulbous, broad-based destructive pattern characterizing verrucous carcinomas of the upper aerodigestive tract was not observed. A statistically significant trend existed between the incidence of invasion and size: 8.5% for medium-large, 23% for large, and 50% for giant (p=0.02). There was no discernable trend in the depth of invasion relative to condyloma size. CONCLUSIONS: Our findings suggest that Löwenstein-Buschke lesions are mega versions of conventional condyloma. Being verrucoid, large and minimally invasive, they can be conceptually regarded as a form of verrucous carcinoma, but they do not display the histologic characteristics of verrucous carcinoma defined in the aerodigestive tract. They exhibit two types of linings: the mucosal type that often shows koilocytotic changes, and the epidermal type that can be difficult to recognize in biopsies. These lesions may be associated with invasive carcinoma, albeit limited in amount.

Evaluation of RNA markers for early detection of cervical neoplasia in exfoliated cervical cells.

Numerous molecular biomarkers have been suggested for early detection of cervical cancer, but their usefulness in routinely collected exfoliated cells remains uncertain. We used quantitative reverse transcription-PCR to evaluate expression of 40 candidate genes as markers for high-grade cervical intraepithelial neoplasia (CIN) in exfoliated cervical cells collected at the time of colposcopy. Samples from the 93 women with CIN3 or cancer were compared with those from 186 women without disease matched (1:2) for age, race, and high-risk human papillomavirus status. Normalized threshold cycles (C(t)) for each gene were analyzed by receiver operating characteristics to determine their diagnostic performance in a split sample validation approach. Six markers were confirmed by an area under the curve >0.6 in both sample sets: claudin 1 (0.75), minichromosome maintenance deficient 5 (0.71) and 7 (0.64), cell division cycle 6 homologue (0.71), antigen identified by monoclonal antibody Ki-67 (0.66), and SHC SH2-domain binding protein 1 (0.61). The sensitivity for individual markers was relatively low and a combination of five genes to a panel resulted in 60% sensitivity with 76% specificity, not positively increasing this performance. Although the results did not indicate superiority of RNA markers for cervical cancer screening, their performance in detecting disease in women referred for colposcopy suggests that the genes and pathways they highlight could be useful in alternative detection formats or in combination with other screening indicators.

Multiple amyloidomas in an HIV patient presented as inguinal and mediastinal masses: a case report diagnosed by fine-needle aspiration.

Systemic amyloidosis can occur rarely as multiple masses with replacement of lymph nodes, causing lymphadenopathy and potentially mimicking neoplasms. We report a case of multiple amyloidomas in the inguinal lymph nodes and mediastinum in a 30-yr-old HIV positive woman with remote history of high grade dysplasia. Abundant amorphous material was obtained on fine-needle aspiration, making metastatic squamous cell carcinoma with abundant keratin a potential differential diagnosis. The prudent use of special stains such as Congo red, crystal violet, and immunohistochemical stains for keratin and kappa and beta light chains can be invaluable in helping to clarify the diagnosis. In patients with chronic inflammation, amyloidomas must be considered in the differential diagnosis of mass lesions so the appropriate work-up can be undertaken to minimize this potential pitfall.

Salivary duct carcinoma metastatic to inguinal lymph node: a case report of salivary duct carcinoma with distant metastasis diagnosed by fine-needle aspiration.

Salivary duct carcinoma (SDC) is a high-grade malignant tumor exhibiting aggressive growth with early regional and distant metastasis. We report a case of SDC in a 53-yr-old male with distant metastasis to an inguinal lymph node. The diagnosis of the primary tumor as well as the metastatic lesion was accomplished by fine-needle aspiration (FNA). Aggressive clinical management appears to be the main therapeutic option for long-term survival. Therefore, establishing an accurate preoperative diagnosis by FNA can have both clinical and prognostic relevance.

Anal cytology in an HIV-positive population: a retrospective analysis.

OBJECTIVE: To retrospectively evaluate cellularity and correlate the presence of columnar cells with specimen interpretation in conventionally prepared anal cytologic smears from an HIV-positive population. STUDY DESIGN: Two cytopathologists and 1 senior cytotechnologist, blinded to the original diagnosis, screened 114 samples from 110 patients collected between 1997 and 2002. One hundred nine males and 1 female were included, age ranging from 23 to 52 years. Discrepancies were reviewed for consensus. The interpretations, cellularity, and presence or absence of columnar cells were noted. The relationships between diagnosis and presence of columnar cells, visible anal lesions, concurrent HIV viral load and CD4+ T-cell counts were assessed. RESULTS: The cytologic findings were as follows: 7, unsatisfactory (6%); 29, negative (25%); 25, atypical squamous cells of undetermined significance (22%); and 53, dysplasia (47%) (42 anal intraepithelial lesion 1 [37%] and 11 anal intraepithelial lesion 2/3 [10%]). Nearly 50% of the smears, 51, showed the presence of columnar cells (45%); 37 of those specimens had some degree of dysplasia (74%). Of the 63 specimens with no columnar cells, 16 (25%) showed dysplasia. Columnar cells were absent from all unsatisfactory specimens. CONCLUSION: A highly significant association between the presence of columnar cells and anal intraepithelial lesion (p<0.001) and a significant association between the presence of columnar cells and atypical cytology when a visible lesion was absent (p=0.0019) were found. No significant relationship was found between the presence/degree of dysplasia and CD4+ T-cell counts or HIV viral load. Lack of clinical follow-up precluded evaluation of the false negative rates in this data set.

Use of second-generation antipsychotics in the acute inpatient management of schizophrenia in the Middle East.

BACKGROUND: Management of acute psychotic episodes in schizophrenic patients remains a significant challenge for clinicians. Despite treatment guidelines recommending that second-generation antipsychotics (SGAs) should be used as monotherapy, first-generation antipsychotics, polypharmacy, and lower than recommended doses are frequently administered in clinical practice. Minimal data exist regarding the use of SGAs in the Middle East. The objective of this study was to examine the discrepancies between current clinical practice and guideline recommendations in the region. METHODS: RECONNECT-S Beta was a multicenter, noninterventional study conducted in Egypt, Kuwait, Saudi Arabia, and the United Arab Emirates to observe the management of schizophrenic patients who were hospitalized due to an acute psychotic episode. Patients underwent one visit on the day of discharge. Demographic and medical history, together with data on antipsychotic treatment and concomitant medication during the hospitalization period and medication recommendations at discharge were recorded. RESULTS: Of the 1,057 patients, 180 (17.0%) and 692 (65.5%) received SGAs as monotherapy and in combination therapy, respectively. Overall, the most frequently administered medications were given orally, and included risperidone (40.3%), olanzapine (32.5%), and quetiapine (24.6%); the doses administered varied between countries and deviated from the recommended guidelines. Upon discharge, 93.9% of patients were prescribed SGAs as maintenance therapy, and 84.8% were prescribed the same medication(s) as during hospitalization. CONCLUSION: Current clinical practice in the Middle East differs from guideline recommendations. Patients frequently received antipsychotics in combination therapy, by various methods of administration, and at doses above and below the recommended guidelines for the management of their acute psychotic episodes.

Phyllodes tumors in African American women.

BACKGROUND: Phyllodes is a rare tumor accounting for less than 1% of all breast neoplasms. Studies defining clinical predictors of malignant phyllodes (MP) are rare and inconsistent. Furthermore, MP occurrence in African American (AA) women has never been analyzed. This study will delineate clinical and pathologic features in AA patients that may reasonably predict the probability of malignancy. METHODS: A retrospective study of clinical records was carried out for 50 AA patients diagnosed with phyllodes tumors (PT) and treated between 1982 and 2012. Patients' charts were analyzed regarding demographics, pathology findings, and treatment. RESULTS: The diagnosis of benign disease was made in 40 (78%), borderline in 3 (6%), and malignancy in 7 (14%) patients; however, 1 patient (2%) had mixed phyllodes with ductal carcinoma in situ. The mean age was significantly different for patients with benign disease (33 years) compared with those with malignancy (54 years; P < .001). The average tumor size was twice as large (11.8 vs 4.1 cm; P = .029) and mitoses were higher with 50% of MPs having greater than 5 per 10 high power fields. Although rare, nodal metastasis, ulceration, and multicentric disease occurred only in MP. CONCLUSIONS: Among AA patients with phyllodes tumors, those with malignant tumors were older and had larger tumors and higher mitotic indices than those with benign disease. AA patients also displayed some of the more rare features of advanced disease and presented with malignancy near the highest reported frequency.

Progression and regression of cervical pap test lesions in an urban AIDS clinic in the combined antiretroviral therapy era: a longitudinal, retrospective study.

Our objective was to evaluate the progression and regression of cervical dysplasia in human immunodeficiency virus (HIV)-positive women during the late antiretroviral era. Risk factors as well as outcomes after treatment of cancerous or precancerous lesions were examined. This is a longitudinal retrospective review of cervical Pap tests performed on HIV-infected women with an intact cervix between 2004 and 2011. Subjects needed over two Pap tests for at least 2 years of follow-up. Progression was defined as those who developed a squamous intraepithelial lesion (SIL), atypical glandular cells (AGC), had low-grade SIL (LSIL) followed by atypical squamous cells-cannot exclude high-grade SIL (ASC-H) or high-grade SIL (HSIL), or cancer. Regression was defined as an initial SIL with two or more subsequent normal Pap tests. Persistence was defined as having an SIL without progression or regression. High-risk human papillomavirus (HPV) testing started in 2006 on atypical squamous cells of undetermined significance (ASCUS) Pap tests. AGC at enrollment were excluded from progression analysis. Of 1,445 screened, 383 patients had over two Pap tests for a 2-year period. Of those, 309 had an intact cervix. The median age was 40 years and CD4+ cell count was 277 cells/mL. Four had AGC at enrollment. A quarter had persistently normal Pap tests, 64 (31%) regressed, and 50 (24%) progressed. Four developed cancer. The only risk factor associated with progression was CD4 count. In those with treated lesions, 24 (59%) had negative Pap tests at the end of follow-up. More studies are needed to evaluate follow-up strategies of LSIL patients, potentially combined with HPV testing. Guidelines for HIV-seropositive women who are in care, have improved CD4, and have persistently negative Pap tests could likely lengthen the follow-up interval.

Galanin immunoreactivity in paragangliomas but not in carcinoid tumors.

Galanin is a 29 to 30-amino acid neuropeptide involved in diverse regulatory effects in the central and peripheral nervous systems. Although galanin has been found in paragangliomas and other tumors, its expression has not been studied in carcinoid tumors arising in various locations. Galanin was detected in 62% (15/24) of adrenal pheochromocytomas, 40% (2/5) of jugulotympanic paragangliomas, and 18% (2/11) of carotid body paragangliomas, but was absent in 4 extra-adrenal pheochromocytomas and 3 metastatic or recurrent paragangliomas. All 26 carcinoid tumors were negative. Galanin may have limited utility as a diagnostic marker alone but would be most useful in conjunction with other immunohistochemical markers for the differential diagnosis of neuroendocrine tumors.

Age-group differences in human papillomavirus types and cofactors for cervical intraepithelial neoplasia 3 among women referred to colposcopy.

BACKGROUND: Recommendations for high-risk human papillomavirus (HR-HPV) testing as an adjunct to cytology for cervical cancer screening differ by age group, because HR-HPV tests lack adequate specificity in women aged <30. Here, we assess age-group differences in HPV types and other risk factors for cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) versus CIN0-2 in women from four colposcopy clinics. METHODS: Women ages 18 to 69 (n = 1,658) were enrolled and completed structured interviews to elicit data on behavioral risk factors prior to their examinations. HPV genotyping was done on exfoliated cervical cell samples. We estimated relative risks (RR) for HPV types and cofactors for CIN3+, overall and stratified by age group. RESULTS: After 2 years of follow-up, we identified 178 CIN3+, 1,305 CIN0-2, and 175 indeterminate outcomes. Nonvaccine HR-HPV types were only associated with CIN3+ among women ≥ 30 (RR = 2.3, 95% CI: 1.5-3.4; <30: RR = 0.9). Among all HR-HPV-positive women, adjusting for age, significant cofactors for CIN3+ included current smoking (RR = 1.5), former smoking (RR = 1.8), regular Pap screening (RR = 0.7), current regular condom use (RR = 0.5), and parity ≥ 5 (RR = 1.6, P(trend) for increasing parity = 0.07). However, the parity association differed by age group (≥ 30: RR = 1.8, P(trend) = 0.008; <30: RR = 0.9; P(trend) =.55). CONCLUSION: Subgroup variation by age in the risk of CIN3+ points to the importance of the timing of exposures in relation to CIN3+ detection. IMPACT: Future screening strategies need to consider natural history and secular trends in cofactor prevalence in the pursuit of appropriately sensitive and specific screening tools applied to appropriate age groups.

Hematologic malignancies of the female genital tract diagnosed on liquid-based Pap test: Cytomorphologic features and review of differential diagnoses.

The female genital tract is rarely the primary site for hematologic malignancies; however, secondary involvement of this anatomic site is common. Primary lymphomas of the gynecologic tract are reported to represent less than 1% of extranodal non-Hodgkin lymphomas (NHL), and the majority of them being B-cell in origin. Diffuse large B-cell lymphoma is the most common subtype, whereas primary extraosseus plasmacytoma of the genital tract is rare.If clinically not suspected, these rare tumors pose a diagnostic challenge both for clinicians and pathologists. Clinical symptoms are often nonspecific and mimic other more common gynecologic malignancies such as squamous cell carcinoma of the cervix or endometrial adenocarcinoma. Although cervico-vaginal (Pap) smear is the primary screening method for cervical squamous cell carcinoma and its precursors, it is far less sensitive for detection of other primary or metastatic malignancies. In this review, we present three cases of hematologic gynecologic malignancies, two cases of primary NHL, and a case of acute myeloid leukemia with relapse as a pelvic mass, all of which were diagnosed on a liquid-based Pap test. In addition, we discuss the morphologic features of differential diagnostic entities of these rare tumors on conventional and liquid-based preparations.

Genital and perianal herpes simplex simulating neoplasia in patients with AIDS.

Genital and perianal herpetic ulcers are common in HIV-infected patients and chronic mucocutaneous ulcers persisting for more than 1 month are the hallmark of active AIDS status. However, atypical clinical manifestations of herpes simplex virus (HSV) may occur in immunocompromised patients presenting as tumor-like nodules or condylomatous or hypertrophic lesions, rather than a classic ulcer. Such unusual presentations raise the risk of misdiagnosis and a delay in appropriate treatment. Here we describe nine immunocompromised HIV-positive patients with CD 4 count ranging from 14-362/mm(3) (mean 170/mm(3)), with unusual tumoral presentation of anogenital herpes. There were six male and three female patients with AIDS with mean duration of HIV infection of 14 years. All of the patients had history of highly active antiretroviral therapy (HAART), with five patients compliant with the therapy at the time of biopsy. Six patients presented with scrotal or vulvar masses and three with perianal nodules. Five patients had adjacent human papilloma virus (HPV)-related lesions. Prior to excision, herpetic lesion was clinically suspected in only three patients and in the rest of the patients a malignant growth was the main clinical concern. The predominant histopathologic finding was dense dermal plasmacytic infiltration with overlying pseudoepitheliomatous hyperplasia, superficial ulcers and classic herpetic inclusions. Patients with AIDS may experience excessive number and size of both primary and reactivated herpetic lesions. The tumoral presentations discussed here are less common, but are often clinically misdiagnosed. It is important to be aware of these unusual presentations to provide a correct diagnosis and prompt, effective treatment for HSV. Several studies suggest that aggressive treatment of HSV in combination with HAART therapy provides a significant survival benefit. Pathobiology mechanisms of unusual and exaggerated tumor-like inflammatory response are not completely elucidated.

Epidemiologic and viral factors associated with cervical neoplasia in HPV-16-positive women.

While infection with high-risk HPV is the most important risk factor for cervical cancer, HPV alone is insufficient. Our purpose was to identify viral and epidemiologic factors associated with cervical disease in HPV-16 DNA-positive women referred to colposcopy. We used a standardized interview to collect epidemiologic data from consenting women. Total nucleic acids from exfoliated cervical cells were used for all viral assays (HPV detection and typing using L1 consensus PCR with line probe hybridization, variant classification by sequencing, viral load and transcript copy determination by quantitative PCR and transcript pattern by nested RT-PCR). Cervical disease was based on colposcopic biopsy. Logistic regression was used to calculate ORs with 95% CIs. There were 115 HPV-16 positive women among 839 enrollees. By univariate analyses, age >25 years (OR = 3.05, 95% CI 1.20-7.76), smoking (OR = 3.0, 95% CI 1.19-7.56), high viral load (OR = 5.27, 95% CI 2.05-13.60), detection of both E6 and E6*I transcripts (OR = 10.0, 95% CI 2.1-47.58) and high transcript copies (OR = 5.56, 95% CI 2.05-13.60) were significant risk factors for CIN III with reference to No CIN/CIN I. Less than a third of the women (31.5%) had prototype HPV-16 detected, and variants showed no association with disease, viral load or transcription. Viral DNA and transcript copies were highly correlated, and the ratio of transcript copies to DNA copies was not changed with disease status. While viral load, transcript copies and transcript pattern were statistically associated with CIN III, none of these measures effectively discriminated between HPV-16 women with disease requiring treatment and those who could be followed. Cellular proliferation and differentiation pathways affected by HPV should be investigated as biomarkers for cervical cancer screening.

Fall 2002.

OBJECTIVE: The Home Study Course is intended for the practicing colposcopist or practitioner who is seeking to develop or enhance his or her colposcopic skills. The goal of the course is to present colposcopic cases that are unusual or instructive in terms of appearance, presentation, or management or that demonstrate new and important knowledge in the area of colposcopy or pathology. Participants may benefit from reading and studying the material or from testing their knowledge by answering the questions. ACCME ACCREDITATION: The American Society for Colposcopy and Cervical Pathology (ASCCP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. The ASCCP designates this continuing medical education activity for 1 credit hour in Category I of the Physician's Recognition Award of the American Medical Association. Credit is available for those who choose to apply. The Home Study Course is planned and produced in accordance with the ACCME's Essential Areas and Elements.

Winter 2003.

OBJECTIVE: The Home Study Course is intended for the practicing colposcopist or practitioner who is seeking to develop or enhance his or her colposcopic skills. The goal of the course is to present colposcopic cases that are unusual or instructive in terms of appearance, presentation, or management or that demonstrate new and important knowledge in the area of colposcopy or pathology. Participants may benefit from reading and studying the material or from testing their knowledge by answering the questions. ACCME ACCREDITATION: The American Society for Colposcopy and Cervical Pathology (ASCCP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. The ASCCP designates this continuing medical education activity for 1 credit hour in Category I of the Physician's Recognition Award of the American Medical Association. Credit is available for those who choose to apply. The Home Study Course is planned and produced in accordance with the ACCME's Essential Areas and Elements.

Correlation and expression of p53, HER-2, vascular endothelial growth factor (VEGF), and e-cadherin in a high-risk breast-cancer population.

BACKGROUND: Many genetic traits common to aggressive breast carcinoma have been identified; yet little is known about the interrelationships of such traits during tumor development, especially in women prone to aggressive cancer. This study examined the expression of four biological markers associated with poor prognosis at each stage of breast cancer progression in primary tumors from women of lower economic status and assessed the relationship between these markers. METHODS: Archived primary breast tumors from 77 patients were assessed by immunohistochemical analysis for expression of human epidermal growth receptor 2 (HER-2), p53, vascular endothelial growth factor (VEGF), and e-cadherin, and the relationships between the expressions of these molecules were studied. RESULTS: Twenty-two (29%) patients had advanced (stage III or IV) disease. HER-2, VEGF, e-cadherin, and p53 signal were positive for 31 (40%), 58 (75%), 63 (82%), and 37 (48%) of patients, respectively. Among the markers tested, only p53 exhibited a significant association between expression and stage of the disease ( P = 0.012). Expression of e-cadherin was positively associated with HER-2 overexpression ( P = 0.004), and high levels of HER-2 occurred with strongly positive e-cadherin tumors. Marginally significant positive associations were observed between HER-2 and p53 signal ( P = 0.06), and between disease stage and e-cadherin expression ( P = 0.08). CONCLUSION: The significant tendency toward expression of e-cadherin in conjunction with HER-2 overexpression in breast cancer is a novel finding. The association of p53 with more advanced stages of cancer emphasizes it as a key participant in metastatic processes in breast cancer. Many genetic traits common to aggressive breast carcinoma have been identified; yet little is known about the interrelationships of such traits during tumor development, especially in women prone to aggressive cancer. This study examined the expression of four biological markers associated with poor prognosis at each stage of breast cancer progression in primary tumors from women of lower economic status and assessed the relationship between these markers.