Performance of cervical cytology and HPV testing for primary cervical cancer screening in Latin America: an analysis within the ESTAMPA study.

Background: Cervical cytology remains widely used as the initial tool in cervical cancer screening worldwide. WHO guidelines recommend replacing cytology with primary HPV testing to reach cervical cancer elimination goals. We assessed the performance of cytology and high-risk HPV testing to detect cervical precancer, cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) among women aged 30-64 years participating in the ESTAMPA study. Methods: Women were screened with cytology and HPV across ESTAMPA study centres in Latin America. Screen-positives were referred to colposcopy with biopsy collection and treatment as needed. Those with no evident precancer were recalled at 18-months for a second HPV test to complete disease ascertainment. Performance indicators for cytology and HPV to detect CIN3+ were estimated. Findings: 30,606 participants with available cytology and HPV results were included in the analysis. A total of 440 histologically confirmed CIN3s and 30 cancers were diagnosed. Cytology sensitivity for CIN3+ was 48.5% (95% CI: 44.0-53.0), whereas HPV testing had a sensitivity of 98.1% (95% CI: 96.3-96.7). Specificity was 96.5% (95% CI: 96.3-96.7) using cytology and 88.7% (95% CI: 88.3-89.0) with HPV. Performance estimates varied substantially by study centre for cytology (ranging from 32.1% to 87.5% for sensitivity and from 89.2% to 99.5% for specificity) while for HPV results were more consistent across sites (96.7%-100% and 83.6-90.8%, respectively). Interpretation: The limited and highly variable sensitivity of cytology strongly supports transition to the more robust and reproducible HPV-based cervical screening to ensure progress towards global cervical cancer elimination targets in Latin America. Funding: IARC/WHO, UNDP, HRP/WHO, NCI and local funders.

High sensitivity and specificity rates of cobas® HPV test as a primary screening test for cervical intraepithelial lesions in a real-world setting.

Cervical carcinoma (CC) is the fourth most common malignancy among women. Screening with Papanicolau smear is linked to a reduction in CC incidence rates when screening programs have been developed. However, this technique has several limitations, including moderate sensitivity rates for detection of cervical preneoplastic HPV-related lesions. In this real-world study, we proposed to evaluate the sensitivity and specificity rates of cobas® test, which amplifies target DNA fragments by polymerase chain reaction and hybridization of nucleic acids for the detection of 14 HR-HPV types in a single analysis) used as primary screening test for CC and preneoplastic lesions in women aged 25-65 years in a large University Hospital in Buenos Aires. A total of 1044 patients were included in the sample (median age: 46 years); sensitivity and specificity rates for the HR-HPV test used as primary screening test were 98.66% (95% confidence interval [95CI]: 97.67-99.3%) and 87.15% (95CI: 84.93-89.15%), respectively. The positive predictive value was 88.47% (95CI: 86.54%-90.42%) and the negative predictive value was 98.48% (95CI: 97.75%-99.23%). The cobas® HR-HPV testing was highly sensitive and specific for the detection of CC and preneoplastic lesions in real practice.

Microbiota unbalance in relation to high-risk human papillomavirus cervical infection.

OBJECTIVES: To assess vaginal dysfunction using basic vaginal states and the presence of lactobacillary microbiota in patients with human papillomavirus (HPV) infection with no squamous intra-epithelial lesions (SIL), with low-grade squamous intra-epithelial lesions (L-SIL), and with high-grade squamous intra-epithelial lesions (H-SIL) or squamous cell carcinoma compared with a control group (HPV-negative); to establish the prevalence of bacterial vaginosis, candidiasis, and trichomoniasis in the different age groups; and to characterize the species of lactobacilli according to the type of lesion. METHODS: A cross-sectional study was carried out of patients who underwent clinical examination and collection of vaginal fornixes to study basic vaginal states and culture. Species identification of lactobacilli was performed by mass spectrometry. The results were analyzed using the χ2 and Fisher's tests; p<0.05 was considered significant. High-risk viral types were determined using a multiplex real-time polymerase chain reaction test. RESULTS: A total of 741 patients were analyzed and divided into three age groups: Group 1 aged 18-24 years (n=138), Group 2 aged 25-50 years (n=456), and Group 3 aged >50 years (n=147). All groups were further divided into an HPV-negative (control) group and an HPV-positive group without lesions, with L-SIL, or with H-SIL/squamous cell carcinoma. The prevalence of unbalanced basic vaginal states in patients with H-SIL/squamous cell carcinoma was 72.7% (p=0.03) in Group 1, 53.1% (p=0.05) in Group 2, and no cases of unbalance were detected in Group 3. The prevalence of bacterial vaginosis in women with H-SIL/squamous cell carcinoma in Group 1 was 54.5% and in Group 2 was 43.7%. Patients with H-SIL/squamous cell carcinoma had a prevalence of 21.4% of Lactobacillus crispatus, 42.9% of L. jensenii, and 14.3% of L. iners. CONCLUSIONS: A greater unbalance of vaginal microbiota was observed in patients with SIL, especially in those with H-SIL/squamous cell carcinoma. In this group, an increase in L. jensenii and L. iners compared with control was found. L. crispatus had a similar prevalence to the control group. It is important to characterize the lactobacilli species since the unbalance alters the vaginal microenvironment and acts as a co-factor in the persistence of HPV infection.

Implementing HPV testing in 9 Latin American countries: The laboratory perspective as observed in the ESTAMPA study.

Background: Replacement of cytology screening with HPV testing is recommended and essential for cervical cancer elimination. HPV testing for primary screening was implemented in 12 laboratories within 9 Latin American countries, as part of the ESTAMPA cervical cancer screening study. Our observations provide information on critical operational aspects for HPV testing implementation in diverse resource settings. Methods: We describe the implementation process of HPV testing in ESTAMPA, focusing on laboratory aspects. We assess the readiness of 12 laboratories to start HPV testing and their continuity capacity to maintain good quality HPV testing until end of recruitment or up to December 2021. Readiness was based on a checklist. Information from the study database; regular meetings and monitoring visits; and a questionnaire on laboratory operational aspects sent in May 2020 were used to assess continuity capacity. Compliance with seven basic requirements (readiness) and eight continuity requirements (continuity capacity) was scored (1 = compliant, 0 = not compliant) and totaled to classify readiness and continuity capacity as very limited, limited, moderate or high. Experiences, challenges, and enablers of the implementation process are also described. Results: Seven of 12 laboratories had high readiness, three moderate readiness, and of two laboratories new to HPV testing, one had limited readiness and the other very limited readiness. Two of seven laboratories with high readiness also showed high continuity capacity, one moderate continuity capacity, and the other four showed limited continuity capacity since they could not maintain good quality HPV testing over time. Among three laboratories with moderate readiness, one kept moderate continuity capacity and two reached high continuity capacity. The two laboratories new to HPV testing achieved high continuity capacity. Based on gained expertise, five laboratories have become part of national screening programs. Conclusion: High readiness of laboratories is an essential part of effective implementation of HPV testing. However, high readiness is insufficient to guarantee HPV testing high continuity capacity, for which a "culture of quality" should be established with regular training, robust monitoring and quality assurance systems tailored to local context. All efforts to strengthen HPV laboratories are valuable and crucial to guarantee effective implementation of HPV-based cervical screening.

Metástasis de carcinoma medular de tiroides en endometrio: reporte de un caso y revisión de la literatura / Metastasis of medullary thyroid carcinoma to the endometrium: A case report and review of the literature

Las metástasis uterinas de tumores extrapélvicos son raras y, cuando el útero se ve involucrado, es usualmente por extensión directa de neoplasias de órganos adyacentes. Se presenta el caso de una mujer de 68 años con antecedente de tiroidectomía total, que concurrió con incontinencia urinaria asociada a episodios de metrorragia. Se le realizó un legrado debido a un engrosamiento endometrial y se reconoció una proliferación de células neoplásicas con núcleos ovales, cromatina en «sal y pimienta», nucléolos evidentes y moderada cantidad de citoplasma eosinófilo, las cuales resultaron positivas con CKAE1/AE3, TTF-1, CEA y calcitonina. Los hallazgos histológicos e inmunohistoquímicos correspondieron a una metástasis de un carcinoma medular de tiroides.Si bien las metástasis en el útero son extremadamente infrecuentes, el sangrado uterino anormal podría ser la única expresión clínica y se debería pensar en ello cuando los antecedentes de la paciente y los hallazgos histológicos no sean característicos de una lesión primaria.(AU)

Uterine metastases from extra pelvic tumors are rare; involvement of the uterus is usually by direct neoplastic extension from adjacent organs. We report the case of a 68-year-old woman with a history of total thyroidectomy. She presented with urinary incontinence associated with episodes of metrorrhagia. Ultrasound showed a thickened endometrium. A legrado was performed and the biopsy revealed a proliferation of neoplastic cells with oval nuclei, «salt and pepper» chromatin, evident nucleoli and a moderate amount of eosinophilic cytoplasm. These cells were positive for CKAE1 / AE3, TTF-1, CEA and calcitonin. The histological and immunohistochemical findings corresponded to a metástasis from a medullary thyroid carcinoma. Although metastatic tumors in the uterus are extremely rare, they may give rise to abnormal uterine bleeding and should be considered when the patient's history and the histological findings are not characteristic of a primary lesion.(AU)

[Metastasis of medullary thyroid carcinoma to the endometrium: A case report and review of the literature]. / Metástasis de carcinoma medular de tiroides en endometrio: reporte de un caso y revisión de la literatura.

Uterine metastases from extra pelvic tumors are rare; involvement of the uterus is usually by direct neoplastic extension from adjacent organs. We report the case of a 68-year-old woman with a history of total thyroidectomy. She presented with urinary incontinence associated with episodes of metrorrhagia. Ultrasound showed a thickened endometrium. A legrado was performed and the biopsy revealed a proliferation of neoplastic cells with oval nuclei, «salt and pepper¼ chromatin, evident nucleoli and a moderate amount of eosinophilic cytoplasm. These cells were positive for CKAE1 / AE3, TTF-1, CEA and calcitonin. The histological and immunohistochemical findings corresponded to a metástasis from a medullary thyroid carcinoma. Although metastatic tumors in the uterus are extremely rare, they may give rise to abnormal uterine bleeding and should be considered when the patient's history and the histological findings are not characteristic of a primary lesion.

[Immunohistochemistry of p16 and p53 in vulvar cancer]. / Inmunohistoquímica de p16 y p53 en cáncer de vulva.

Squamous cell carcinoma of the vulva may develop in association or independently of HPV infection. The relationship between pathogenesis, classification, immunohistochemical profile and prognosis has been studied in the literature with some discrepancies. The aim of this study was to observe the classical association of keratinizing carcinomas with the absence of HPV infection and warty and basaloid carcinomas with the presence of this virus. Therefore, we reviewed the clinic, morphology, and immunophenotype of 39 cases. The tumors were histologically classified into classic keratinizing squamous carcinoma (30), warty (5) and basaloid (4). In the statistical analysis, diffuse expression with p16 was significantly associated with younger age (p = 0.0025), presence of high-grade intraepithelial lesion (p < 0.0001), koilocytosis (p = 0.02), and morphological subtype (p = 0.02), and was inversely associated with the expression of p53 (p < 0.0001) and the presence of lichen sclerosus (p = 0.0051). It is curious that 4 keratinizing carcinomas of the cases studied presented coexpression of p16 and p53. Only one warty tumor was negative for p16 and positive for p53, and 9 keratinizing tumors were positive for p16 and negative for p53. Although these findings show that the use of hematoxylin and eosin could correctly define tumors associated with HPV, we strongly suggest the performance of immunohistochemistry, especially in squamous keratinizing classic carcinomas in young patients with a history of HPV.

El carcinoma escamoso vulvar puede desarrollarse de manera asociada o independiente a la infección por HPV. La relación entre la patogénesis, la clasificación, el perfil inmunohistoquímico, y el pronóstico ha sido estudiada con algunas discrepancias. El objetivo del trabajo fue observar la concordancia clásicamente descripta que asocia a los carcinomas queratinizantes con la ausencia de infección por HPV y a los carcinomas warty y basaloides con la presencia de dicho virus. Para ello, revisamos la clínica, la morfología y el inmunofenotipo de 39 casos de nuestro hospital. Los tumores fueron clasificados histológicamente en carcinomas escamosos queratinizantes clásicos (30), warty (5) y basaloides (4). En el análisis estadístico la expresión de p16 fue asociada de manera significativa con una edad menor al momento del diagnóstico (p = 0.0025), presencia de lesión intraepitelial escamosa de alto grado (p < 0.0001), coilocitosis (p = 0.02), y subtipo morfológico (p = 0.02); y fue inversamente asociado con la expresión de p53 (p < 0.0001) y con el liquen escleroso (p = 0.0051). Resulta peculiar que, de los casos estudiados, 4 carcinomas queratinizantes coexpresaron p16 y p53. Un solo tumor de tipo warty resultó negativo para p16 y positivo para p53, y 9 queratinizantes resultaron positivos para p16 y negativos para p53. Si bien estos hallazgos indican que con la sola utilización de la hematoxilina y eosina podrían definirse de manera correcta los tumores asociados al HPV, sugerimos fuertemente la realización de inmunohistoquímica, especialmente en carcinomas escamosos queratinizantes en pacientes jóvenes o con historia de HPV.

Inmunohistoquímica de p16 y p53 en cáncer de vulva / Immunohistochemistry of p16 and p53 in vulvar cancer

El carcinoma escamoso vulvar puede desarrollarse de manera asociada o independiente a la infección por HPV. La relación entre la patogénesis, la clasificación, el perfil inmunohistoquímico, y el pronóstico ha sido estudiada con algunas discrepancias. El objetivo del trabajo fue observar la concordancia clásicamente descripta que asocia a los carcinomas queratinizantes con la ausencia de infección por HPV y a los carcinomas warty y basaloides con la presencia de dicho virus. Para ello, revisamos la clínica, la morfología y el inmunofenotipo de 39 casos de nuestro hospital. Los tumores fueron clasificados histológicamente en carcinomas escamosos queratinizantes clásicos (30), warty (5) y basaloides (4). En el análisis estadístico la expresión de p16 fue asociada de manera significativa con una edad menor al momento del diagnóstico (p = 0.0025), presencia de lesión intraepitelial escamosa de alto grado (p < 0.0001), coilocitosis (p = 0.02), y subtipo morfológico (p = 0.02); y fue inversamente asociado con la expresión de p53 (p < 0.0001) y con el liquen escleroso (p = 0.0051). Resulta peculiar que, de los casos estudiados, 4 carcinomas queratinizantes coexpresaron p16 y p53. Un solo tumor de tipo warty resultó negativo para p16 y positivo para p53, y 9 queratinizantes resultaron positivos para p16 y negativos para p53. Si bien estos hallazgos indican que con la sola utilización de la hematoxilina y eosina podrían definirse de manera correcta los tumores asociados al HPV, sugerimos fuertemente la realización de inmunohistoquímica, especialmente en carcinomas escamosos queratinizantes en pacientes jóvenes o con historia de HPV.

Squamous cell carcinoma of the vulva may develop in association or independently of HPV infection. The relationship between pathogenesis, classification, immunohistochemical profile and prognosis has been studied in the literature with some discrepancies. The aim of this study was to observe the classical association of keratinizing carcinomas with the absence of HPV infection and warty and basaloid carcinomas with the presence of this virus. Therefore, we reviewed the clinic, morphology, and immunophenotype of 39 cases. The tumors were histologically classified into classic keratinizing squamous carcinoma (30), warty (5) and basaloid (4). In the statistical analysis, diffuse expression with p16 was significantly associated with younger age (p = 0.0025), presence of high-grade intraepithelial lesion (p < 0.0001), koilocytosis (p = 0.02), and morphological subtype (p = 0.02), and was inversely associated with the expression of p53 (p < 0.0001) and the presence of lichen sclerosus (p = 0.0051). It is curious that 4 keratinizing carcinomas of the cases studied presented coexpression of p16 and p53. Only one warty tumor was negative for p16 and positive for p53, and 9 keratinizing tumors were positive for p16 and negative for p53. Although these findings show that the use of hematoxylin and eosin could correctly define tumors associated with HPV, we strongly suggest the performance of immunohistochemistry, especially in squamous keratinizing classic carcinomas in young patients with a history of HPV.

Carcinoma micropapilar invasivo de mama: nuestra experiencia en el Hospital de Clínicas José de San Martín / Micropapillary invasive breast carcinoma: our experience at the Hospital de Clínicas José de San Martín

Introducción: El carcinoma micropapilar invasivo de la mama (CMI) es una variante agresivapoco frecuente caracterizada por gran linfotropismo y alta frecuencia de metástasis ganglionares. Se correlaciona con tumores con alto grado histológico. La expresión de receptores hormonales es similar al carcinoma ductal y el HER2/neu se encuentra elevado en mayor proporción. Objetivos: Describir nuestra experiencia con los casos de CMI diagnosticados en el servicio del hospital, detallando los factores de pronóstico y predicción de tratamientos presentes en cada caso. Material y métodos: Se analizaron 26 casos de CMI diagnosticados entre los años 2000 y 2012 en la Sección Patología Mamaria del Hospital de Clínicas José de San Martín. Resultados: De 878 pacientes, 26 casos presentaron CMI (2,96%), edad media de 66 años (37-87 años). El tamaño tumoral varió de 0,4 a 10,0 cm (mediana de 2,1 cm). El 47,6% se presentaron clínicamente como estadio III; 12 casos eran G2 (46,1%) y 14 casos G3 (53,9%). Presentó invasión linfovascular el 73% de los casos. Presentaron compromiso ganglionar 13/19 pacientes (68,4%). Los receptores de estrógeno fueron positivos en el 100% de los casos y los de progesterona en el 63,6%. El HER2/neu fue positivo en 30% de los casos (6/20). El Ki67 fue evaluado en 6 casos, siendo positivo en el 50% (3 casos). Conclusión: El CMI se manifiesta como un tumor altamente agresivo. Se presenta clínicamente con estadios avanzados, alto grado histológico y marcada invasión linfovascular del estroma, alta expresión positiva para receptores hormonales y un nivel algo superior, con respecto al carcinoma ductal, de inmunorreactividad para HER2/neu (30% vs. 15%).

Argentophilic nucleolus organizer region as a proliferation marker in cervical intraepithelial neoplasia grade 1 of the uterine cervix.

AIM: p16INK4a and argentophilic nucleolus organizer region (AgNOR) can be used as markers for progression of cervical intraepithelial neoplasia grade 1 (CIN1) of the uterine cervix. Our objective was to study the predictive value of the AgNOR technique as a progression marker of CIN1 and its correlation with p16INK4A. MATERIAL AND METHODS: One uterine cervix biopsy from each of 75 patients with diagnosis of CIN1 was selected. All of these patients underwent a second biopsy, and these were also used for the study. RESULTS: The second biopsies showed: regression (20 patients), persistent CIN1 (38 patients), progression to CIN2 (10 patients) and progression to CIN3 (seven patients). p16INK4A showed reactivity in 67 of the 75 first CIN1 biopsies: 12 of the 20 cases that cleared the lesions and the 55 cases with persistent or progressive lesions were positive for p16INK4a (specificity: 40%; sensitivity: 100%; positive predictive value [PPV]: 82%; negative predictive value [NPV]: 100%). Samples with AgNOR areas less than 3.0 µ(2) returned in all cases, but patients whose lesions persisted or progressed to CIN2/CIN3, showed AgNOR areas greater than 3.0 µ(2) in 50/55 cases (specificity: 100%; sensitivity: 91%; PPV: 100%; NPV: 80%). CONCLUSIONS: p16INK4a is expressed in a high percentage of returning lesions. AgNOR might be a better marker of proliferation of CIN1 than p16INK4a (PPV = 100%), which means that a value greater than 3.0 µ(2) indicates the persistence or progression of the lesion. As its NPV is 80%, a value of AgNOR area less than 3.0 µ(2) in CIN1 leaves a margin of doubt about the future behavior of the lesion.