Underscreened Women Remain Overrepresented in the Pool of Cervical Cancer Cases in Spain: A Need to Rethink the Screening Interventions.

OBJECTIVE: Audit of women with invasive cervical cancer (CC) is critical for quality control within screening activities. We analysed the screening history in the 10 years preceding the study entry in women with and without CC during 2000-2011. METHODS: 323 women with CC from six pathology departments in Catalonia (Spain) and 23,782 women with negative cytology were compared. Age, previous history of cytologies, and histological type and FIGO stage were collected from the pathology registries. Logistic regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals (CI95%). RESULTS: History of cytology was registered in 26.2% of CC cases and in 78% of the control women (P < 0.0001) and its frequency decreased with increasing age. Compared to women with squamous cell carcinoma, adenocarcinoma cases were significantly more likely to have a cytology within the 3-year interval preceding cancer diagnosis (OR = 2.6 CI 95%: 1.2-5.6) and to have normal cytology results in previous screenings (OR = 2.4 CI 95%: 1.2-4.5). FIGO II-IV cases were more common among older women (older than 60 years). CONCLUSIONS: Absence of prior screening history was extremely common among CC cases compared to controls. Organized actions to reduce underscreened women and use of highly sensitive HPV-based tests could be important to reduce CC burden.

Protecting the underscreened women in developed countries: the value of HPV test.

BACKGROUND: Poor attendance to cervical cancer (CC) screening is a major risk factor for CC. Efforts to capture underscreened women are considerable and once women agree to participate, the provision of longitudinal validity of the screening test is of paramount relevance. We evaluate the addition of high risk HPV test (HPV) to cervical cytology as a primary screening test among underscreened women in the longitudinal prediction of intraepithelial lesions grade 2 or worse (CIN2+). METHODS: Women were included in the study if they were older than 39 years and with no evidence of cervical cytology in the previous five years within the Public Primary Health Care System in Catalonia (Spain). 1,832 underscreened women from eight public primary health areas were identified during 2007-2008 and followed-up for over three years to estimate longitudinal detection of CIN2+. Accuracy of each screening test and the combination of both to detect CIN2+ was estimated. The risk of developing CIN2+ lesions according to histology data by cytology and HPV test results at baseline was estimated using the Kaplan-Meier method. RESULTS: At baseline, 6.7% of participants were HPV positive, 2.2% had an abnormal cytology and 1.3% had both tests positive. At the end of follow-up, 18 out of 767 (2.3%) underscreened women had a CIN2+, two of which were invasive CC. The three-year longitudinal sensitivity and specificity estimates to detect CIN2+ were 90.5% and 93.0% for HPV test and 38.2% and 97.8% for cytology. The negative predictive value was >99.0% for each test. No additional gains in validity parameters of HPV test were observed when adding cytology as co-test. The referral to colposcopy was higher for HPV but generated 53% higher detection of CIN2+ compared to cytology. CONCLUSIONS: Underscreened women had high burden of cervical disease. Primary HPV screening followed by cytology triage could be the optimal strategy to identify CIN2+ leading to longer and safe screen intervals.

Prediction of cervical intraepithelial neoplasia grade 2+ (CIN2+) using HPV DNA testing after a diagnosis of atypical squamous cell of undetermined significance (ASC-US) in Catalonia, Spain.

BACKGROUND: A protocol for cervical cancer screening among sexually active women 25 to 65 years of age was introduced in 2006 in Catalonia, Spain to increase coverage and to recommend a 3-year-interval between screening cytology. In addition, Human Papillomavirus (HPV) was offered as a triage test for women with a diagnosis of atypical squamous cells of undetermined significance (ASC-US). HPV testing was recommended within 3 months of ASC-US diagnosis. According to protocol, HPV negative women were referred to regular screening including a cytological exam every 3 years while HPV positive women were referred to colposcopy and closer follow-up. We evaluated the implementation of the protocol and the prediction of HPV testing as a triage tool for cervical intraepithelial lesions grade two or worse (CIN2+) in women with a cytological diagnosis of ASC-US. METHODS: During 2007-08 a total of 611 women from five reference laboratories in Catalonia with a novel diagnosis of ASC-US were referred for high risk HPV (hrHPV) triage using high risk Hybrid Capture version 2. Using routine record linkage data, women were followed for 3 years to evaluate hrHPV testing efficacy for predicting CIN2+ cases. Logistic regression analysis was used to estimate the odds ratio for CIN2 +. RESULTS: Among the 611 women diagnosed with ASC-US, 493 (80.7%) had at least one follow-up visit during the study period. hrHPV was detected in 48.3% of the women at study entry (mean age 35.2 years). hrHPV positivity decreased with increasing age from 72.6% among women younger than 25 years to 31.6% in women older than 54 years (p < 0.01). At the end of the 3 years follow-up period, 37 women with a diagnosis of CIN2+ (18 CIN2, 16 CIN3, 2 cancers, and 1 with high squamous intraepithelial lesions--HSIL) were identified and all but one had a hrHPV positive test at study entry. Sensitivity to detect CIN2+ of hrHPV was 97.2% (95%confidence interval (CI) = 85.5-99.9) and specificity was 68.3% (95%CI = 63.1-73.2). The odds ratio for CIN2+ was 45.3 (95% CI: 6.2-333.0), when among ASC-US hrHPV positive women were compared to ASC-US hrHPV negative women. CONCLUSIONS: Triage of ASC-US with hrHPV testing showed a high sensitivity for the detection of CIN2+ and a high negative predictive value after 3 years of follow-up. The results of this study are in line with the current guidelines for triage of women with ASC-US in the target age range of 25-65. Non adherence to guidelines will lead to unnecessary medical interventions. Further investigation is needed to improve specificity of ASC-US triage.

Microsatellite instability of the colorectal carcinoma can be predicted in the conventional pathologic examination. A prospective multicentric study and the statistical analysis of 615 cases consolidate our previously proposed logistic regression model.

High microsatellite instability (MSI-H) allows the identification of a subset of colorectal carcinomas associated with good prognosis and a higher incidence of Lynch syndrome. The aim of this work was to assess the interobserver variability and optimize our MSI-H prediction model previously published based on phenotypic features.The validation series collected from five different hospitals included 265 primary colorectal carcinomas from the same number of patients. The eight clinicopathological parameters that integrate our original model were evaluated in the corresponding centers. Homogeneity assessment revealed significant differences between hospitals in the estimation of the growth pattern, presence of Crohn-like reaction, percentage of cribriform structures, and Ki-67 positivity. Despite this observation, our model was globally able to predict MSI-H with a negative predictive value of 97.0%. The optimization studies were carried out with 615 cases and resulted in a new prediction model RERtest8, which includes the presence of tumor infiltrating lymphocytes at the expense of the percentage of cribriform structures. This refined model achieves a negative predictive value of 97.9% that is maintained even when the immunohistochemical parameters are left out, RERtest6. The high negative predictive value achieved by our models allows the reduction of the cases to be tested for MSI to less than 10%. Furthermore, the easy evaluation of the parameters included in the model renders it a useful tool for the routine practice and can reinforce other published models and the current clinical protocols to detect the subset of colorectal cancer patients bearing hereditary nonpolyposis colorectal cancers risk and/or MSI-H phenotype.

Carcinoma microinvasivo de mama: estudio clinicopatológico de 18 casos / Microinvasive breast carcinoma: a clinicopathological profile of 18 cases

Introducción: La definición exacta del carcinoma microinvasivo de mama sigue siendo problemática, y su comportamiento clínico incierto. Hemos estudiado de forma retrospectiva 38 casos con el diagnostico de carcinoma microinvasivo realizado en diversas instituciones, según los criterios de Silver y Tavassoli. Material y métodos: Describimos las características clinicopatológicas y la reproducibilidad del diagnostico de microinvasion, siguiendo los criterios predeterminados. También estudiamos el valor de la p63 y de la calponina, para establecer la integridad de la capa mioepitelial. Resultados: Los casos fueron revisados por dos de los autores (FG, VM) y reclasificados como carcinoma microinvasivo en 18 casos (47%), microinvasión dudosa, 1 caso, carcinoma ductal in situ (DCIS) con el pseudoinvasión, 11 casos (28,9%), y carcinoma ductal invasor pT1a y pT1b en 8 casos (21,6%). El tamaño del DCIS asociado varió entre 7 y 80 mm. En once casos solo había un foco de microinvasión, los otros casos demostraron dos o tres focos de microinvasión. Dos casos mostraron invasión vascular como la única evidencia del microinvasión. El estudio immunohistoquímico con la calponina y la p63 fue útil en la diagnosis en el 50% de los casos. La axila se extirpó en 15 casos, con un solo ganglio positivo (6,6%). El seguimiento ha oscilado entre 3-120 meses (promedio de 42 meses) con sólo una recidiva local sobre la cicatriz por CDIS a los 9 meses. Conclusiones: El sobrediagnóstico histológico es uno de los problemas de esta entidad. Unos criterios morfológicos estrictos y el uso de la inmunohistoquímica es útil en el diagnóstico diferencial con el CDIS y el carcinoma ductal infiltrante. La incidencia de las recurrencias locales y la metástasis ganglionar son bajas y usualmente se asocian a CDIS de alto grado con necrosis. La extirpación del ganglio centinela puede estar indicada en casos de CDIS con microinvasión

Introduction: The exact definition of microinvasive breast carcinoma remains problematic, and its clinical behavior is uncertain. We have studied retrospectively 38 cases with the diagnosis of microinvasive carcinoma made in different institutions, according to the criteria of Silver and Tavassoli. Material and Methods: We describe the clinico-pathologic characteristics and the reproducibility of the diagnosis of microinvasion, following predetermined criteria. We also study the value of immunohistochemical stains with p63 and calponin, to establish the integrity of the myoepithelial layer. Results: The cases were reviewed by two of the authors (FG, VM) and reclassified as microinvasive carcinoma, 18 cases (47%), doubtful microinvasion, 1 case, ductal carcinoma in situ (DCIS) with pseudoinvasion, 11 cases (28.9%), and invasive ductal carcinoma pT1a and pT1b, 8 cases (21.6%).The size of the associated DCIS varied between 7 and 80 mms. In eleven cases one single focus of microinvasion was found, the other cases showed two or three foci of microinvasion. Two cases showed angiolymphatic invasion, as the only evidence of microinvasion. Immunohistochemistry with calponin and p63 was helpful in the diagnosis of microinvasion in 50% of the cases. Axillary lymph nodes were obtained in 15 cases, and a single positive lymph node was found. One patient recurred as DCIS in the surgical scar nine months after surgery. The other patients were disease free after a variable follow-up, between 3 and 120 months (average 42 months). Conclusions: Microinvasive breast carcinoma is often overdiagnosed histologically. The implementation of strict morphological criteria and the use of immunohistochemistry may be helpful in the differential diagnosis with DCIS and invasive ductal carcinoma. The incidence of local recurrence and lymph node metastases is low, and it is usually associated with the presence of high grade DCIS with necrosis. Sentinel lymph node biopsy may be indicated in cases of DCIS with microinvasion (AU)

Historia de cribado en mujeres con cáncer infiltrante de cuello uterino / Screening history in women with infiltrating uterine cancer

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