DeepHistoClass: A Novel Strategy for Confident Classification of Immunohistochemistry Images Using Deep Learning.

A multitude of efforts worldwide aim to create a single-cell reference map of the human body, for fundamental understanding of human health, molecular medicine, and targeted treatment. Antibody-based proteomics using immunohistochemistry (IHC) has proven to be an excellent technology for integration with large-scale single-cell transcriptomics datasets. The golden standard for evaluation of IHC staining patterns is manual annotation, which is expensive and may lead to subjective errors. Artificial intelligence holds much promise for efficient and accurate pattern recognition, but confidence in prediction needs to be addressed. Here, the aim was to present a reliable and comprehensive framework for automated annotation of IHC images. We developed a multilabel classification of 7848 complex IHC images of human testis corresponding to 2794 unique proteins, generated as part of the Human Protein Atlas (HPA) project. Manual annotation data for eight different cell types was generated as a basis for training and testing a proposed Hybrid Bayesian Neural Network. By combining the deep learning model with a novel uncertainty metric, DeepHistoClass (DHC) Confidence Score, the average diagnostic performance improved from 86.9% to 96.3%. This metric not only reveals which images are reliably classified by the model, but can also be utilized for identification of manual annotation errors. The proposed streamlined workflow can be developed further for other tissue types in health and disease and has important implications for digital pathology initiatives or large-scale protein mapping efforts such as the HPA project.

Medical Devices; Hematology and Pathology Devices; Classification of Lynch Syndrome Test Systems. Final order.

The Food and Drug Administration (FDA or we) is classifying Lynch syndrome test systems into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the Lynch syndrome test systems' classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens.

Parotid gland adenocarcinoma in a cow: case report / Adenocarcinoma de glândula parótida em vaca: relato de caso

A 9-year-old Girolando dairy cow, weighing 400kg, with a history of increased volume in the right parotid region, which extended to the submandibular region, was assisted. Fine needle aspiration cytology was performed, and the cytological findings were consistent with malignant neoplasm of epithelial origin (carcinoma). Because of the unfavorable prognosis, the animal was euthanized and submitted to an anatomopathological examination. Samples of the increased parotid and affected lymph nodes were collected for histopathological evaluation. The microscopic changes were accentuated features of anaplasia, moderate cell proliferation, atypical mitotic figures, and necrosis. Stroma ranged from delicate to scirrhous, and the tumor boundaries were not distinct. These findings substantiated the preliminary histomorphological diagnosis of undifferentiated carcinoma with metastasis in lymph nodes. Immunohistochemical tests were performed with anti-CK Pan (clone AE1AE3), anti-CK HMW (clone 34ßE12), anti-CK19 (clone RCK108), anti-vimentin (clone V9), anti-S100 (polyclonal), and anti-androgen (polyclonal) antibodies. The immunophenotype favored the diagnosis of salivary gland adenocarcinoma. Despite the rareness in cattle, salivary gland adenocarcinoma should be considered in the differential diagnosis of diseases that occur with increased volume in the head, lymphadenopathy, drooling, dysphagia, and progressive weight loss.(AU)

Foi atendida uma vaca da raça Girolando, de nove anos de idade, de aptidão leiteira, pesando aproximadamente 400kg e com histórico de aumento de volume na região parotídea e submandibular direita. Diante do prognóstico desfavorável, o animal foi submetido à eutanásia e encaminhado para exame anatomopatológico. Fragmentos da glândula parótida e dos linfonodos alterados foram colhidos e encaminhados para exame histopatológico. À avaliação microscópica, observaram-se acentuada anaplasia, moderada proliferação celular, figuras de mitose atípicas e focos de necrose. O estroma variava de delicado a esquirroso e os limites do tumor eram imprecisos. Esses achados fundamentaram o diagnóstico de carcinoma indiferenciado com metástase em linfonodos. No exame imuno-histoquímico, foram utilizados anticorpos primários monoclonais anti-CK Pan (clone AE1AE3), anti-CK alto peso molecular (clone 34ßE12), anti-CK19 (clone RCK108), antivimentina (clone V9), anti-S100 (policlonal) e antirreceptor de andrógenos (policlonal). As células neoplásicas apresentaram imunomarcação para todos os anticorpos testados, resultado que favorece o diagnóstico de adenocarcinoma de glândula salivar. Embora raro em bovinos, o adenocarcinoma de glândula salivar deve ser considerado no diagnóstico diferencial de doenças que cursam com aumento de volume na cabeça, linfadenopatia salivação, disfagia e emagrecimento progressivo.(AU)

Sarcoma sinovial de pleura en paciente masculino de 72 años de edad / No disponible

El sarcoma sinovial de pleura es una neoplasia poco frecuente que representa el 0,5% de los tumores malignos del pulmón. Se origina tras una translocación del cromosoma 18 y se cree que deriva de células mesenquimales pluripotenciales. Afecta principalmente a adultos jóvenes sin una clara predisposición de sexo. Se clasifica histológicamente en cuatro tipos: fusiforme, epitelioide, bifásico y pobremente diferenciado. El estudio inmunohistoquímico del tejido es fundamental para realizar el diagnóstico, mostrando reactividad positiva a la citoqueratina y antígeno epitelial de membrana. El pronóstico de la enfermedad es malo, con una tasa de supervivencia a los 5 años del 50%. Aunque no existe un consenso de cómo tratar esta patología, la extirpación quirúrgica total de la lesión es la opción terapéutica más utilizada y en algunos casos se utiliza radioterapia y quimioterapia adyuvante

Synovial sarcoma of the pleura is a rare neoplasia that represents 0.5% of lung malign tumors. It originates after a translocation of the 18th chromosome and it is believed that derives from pluripotent mesenchymal cells. It usually affects young adults without a clear sex predisposition. The histological classification consist in four types: monophasic spindle cell, monophasic epithelial, biphasic and poorly differentiated type. The immunohistochemistry study of the tissue is fundamental to make the diagnosis, showing positive reaction to cytokeratin and epithelial membrane antigen. The prognosis of the disease is poor, with a 50% five year survival rate. Even that doesn’t exist a consent to treat this pathology, the complete surgical removal of the tumor is the preferred therapeutic option and in some cases, adjuvant radiotherapy and chemotherapy is indicated

Classificação de coloração imuno-histoquímica combinando cor e textura como descritor / Staining Immunohistochemistry classification blending color and texture as descriptor

O presente trabalho teve por objetivo demonstrar a melhora no desempenho da classificação de coloração imuno-histoquímica em imagens microscópicas, utilizando a abordagem de aprendizado supervisionada que emprega a projeção polinomial da distância de Mahalanobis. Foi definido um descritor de características híbrido, combinando core textura baseada no método Local Binary Pattern, proporcionado inicialmente um descritor 23-dimensional para cada píxel. Uma análise de componentes principais foi realizada e um segundo descritor 12-dimensional foi empregado na avaliação. Os testes foram realizados em imagens e metadados obtidos no The Human Protein Atlas, avaliando uma série de medidas de acerto e erro. Com os resultados encontrados percebeu-se que a utilização do descritor híbrido tornou o processo de classificação mais específico e restritivo nas predições positivas.

This study aimed to demonstrate the improvement in performance of immunohistochemical staining classification in microscopic images using a supervised learning approach that employs the polynomial projection of the Mahalanobis distance. A hybrid feature descriptor was defined by combining color and texture based on Local Binary Pattern method, initially provided a 23-dimensional descriptor, for each pixel. A principal component analysis was performed and a second 12-dimensional descriptor was used in the assay. The tests were performed on images and metadata, obtained on The Human Protein Atlas. With the results it can be seen that the use of hybrid descriptor has made the classification process more specific and restrictive on the positive predictions.

Participação da via Notch em lesões labiais fotoinduzidas / Participation of the Notch pathway in photoinduced lip lesions

A intensa exposição ao Sol sujeita o lábio, principalmente o inferior, aos danos provocados pela absorção de radiação ultravioleta (UV). O carcinoma epidermoide é a neoplasia maligna que se desenvolve nos lábios após exposição crônica prolongada aos raios UV e acredita-se que todos os casos sejam precedidos pela desordem potencialmente maligna denominada queilite actínica. Ambas as lesões são causados pelos efeitos nocivos da radiação UV agindo diretamente sobre o DNA, por meio do fenômeno da fotocarcinogênese. Nesse processo, a radiação provoca mutações que são capazes de causar a iniciação, progressão e a promoção de neoplasias. No entanto, é também importante considerar que outros eventos moleculares, além das mutações, estão envolvidos na iniciação e progressão do câncer. Alterações moleculares com ganho ou perda de função de componentes da via de sinalização Notch estão envolvidas em diferentes tipos de cânceres hematológicos e sólidos. Entretanto, a participação da sinalização Notch em câncer de lábio ainda é desconhecida.

Assim, o objetivo desse trabalho foi investigar se a via Notch está relacionada às lesões de queilite actínica e de carcinoma epidermoide de lábio e sua participação na fotocarcinogênese bucal. Para isso, foram utilizados 45 casos de queilite actínica, 15 casos de carcinoma epidermoide de lábio e 05 casos de lábio com aspecto de normalidade, nos quais foi analisada a expressão de Notch1 e Jagged1 por meio da técnica de imuno-histoquímica. Os resultados demonstraram que houve perda da expressão de Notch1 em 40% dos carcinomas epidermoides de lábio, sugerindo que a expressão reduzida de Notch1 pode converter os queratinócitos a um estado ativado e imaturo. Observou-se ainda, diferença nos padrões de marcação de Nocth1 e Jagged1 nas células epiteliais sugerindo que o sinal da via Notch seja transmitido a partir de uma célula apical para uma célula basal devido a localização das células que expressam o receptor e das que expressam o ligante. Concluiu-se, assim, que os resultados imuno-histoquímicos não apontam a uma regulação diferencial da expressão da proteína Notch1 e Jagged1 em lesões UV induzidas.

The intense exposure to the sun subject the lips, particularly the lower, the damage caused by the absorption of ultraviolet (UV) radiation. The squamous cell carcinoma is a malignant tumor that develops on the lips after prolonged chronic exposure to UV rays and it is believed that all cases are preceded by potentially malignant disorder called actinic cheilitis. Both lesions are caused by the harmful effects of UV radiation acting directly on the DNA, through the phenomenon of photocarcinogenesis. In this process, the radiation causes mutations that are capable of causing the initiation, progression and promotion of cancer. However, it is also important to consider that other molecular events, apart from the mutations are involved in the initiation and progression of cancer. Molecular abnormalities with gain or loss of Notch pathway components function are involved in several types of hematological and solid cancer. However,

the participation of Notch signaling in lip cancer is still unknown. The objective of this study was to investigate whether the Notch pathway is related to injuries actinic cheilitis and squamous cell carcinoma of the lip and participation in oral photocarcinogenesis. For this, were used 45 cases of actinic cheilitis, 15 cases of squamous cell carcinoma of the lip and lip 05 cases with normal aspect in which we analyzed the expression of Notch1 and Jagged1 by immunohistochemistry. The results showed loss of Notch1 expression in 40% of squamous cell carcinomas of the lip, suggesting that reduced expression of Notch1 can convert to an activated keratinocytes and immature state. There was also a difference in labeling patterns of Notch 1 and Jagged1 epithelial cells suggesting that the Notch pathway signal is transmitted from an apical cell to a basal cell due to localization of cells expressing the receptor and expressing the ligand. In summary, the immunohistochemical results do not show a differential regulation of Notch 1 and Jagged1 expression in UV induced lesions.

Descripción de una cohorte de pacientes con cáncer de mama triple-negativo subtipo basal-like, atendidas en el Instituto Nacional de Cancerología y en el Hospital de San José durante el periodo 2006-2008 / Cohort description of patients with triple-negative basal-like subtype breast cancer treated at the National Cancer Institute and the San José Hospital from 2006 to 2008

Objetivos: Establecer la prevalencia y describir las características clínico-patológicas de las pacientes con cáncer de mama triple-negativo subtipo (basal-like y no basal-like) mediante técnicas de inmunohistoquímica que fueron atendidas en el Instituto Nacional de Cancerología (INC) y el Hospital San José (HSJ) durante el periodo 2006- 2008. Métodos: Se realizó un estudio descriptivo de corte transversal, en mujeres mayores de 17 años con diagnóstico histológico confirmado de adenocarcinoma de mama. Se excluyó a las pacientes cuyos bloques de parafina no se conservaron, o a quienes no se les pudieron realizar todos los marcadores inmunohistoquímicos requeridos por el estudio, y se procedió a realizar los marcadores de inmunohistoquímica considerados en el estudio (EFGR, CK5, CK6, S100, P65, CK 14). Se procesaron las muestras siguiendo las recomendaciones de la casa matriz. Se procedió a analizar la información con el programa estadístico Stata10. Resultados: Un total de 1922 casos de cáncer de mama invasor fueron diagnosticados en el periodo comprendido 2006-2008 de los cuales fueron identificados 154 casos de tumores triple negativos (RE negativo, RP negativo, HER-2 Negativo). De estos casos se obtuvo información completa de 84 casos. 50 (59,52%) casos corresponden al tipo basal-like, mientras que 34 (40,48%) corresponden a tumores no basal-like. Conclusiones: El presente estudio es el primero en Colombia que busca determinar mediante inmunohistoquímica la prevalencia del cáncer de mama triple-negativo de tipo basal-like en población colombiana; se halló así una prevalencia del 8,01%, porcentaje que se encuentra por debajo de lo reportado en la literatura mundial (11,9%-25%).

Objectives: To use immunohistochemistry to provide a description of and to ascertain the prevalence of clinical-pathological characteristics in patients with triple-negative (basal-like and non basal-like) subtype breast cancer treated at the National Cancer Institute (NCI) and the San José Hospital (SJH) from 2006 to 2008. Methods: A descriptive cross sectional study was carried out among women over 17 years of age with confirmed diagnosis of breast adenocarcinoma. Patients whose paraffin blocks were not preserved and those on whom it was not possible to carry out the entirety of the immunohistochemical markers requisite for this study were excluded before collection of the immunohistochemical markers considered essential for this study (EFGR, CK5, CK6, S100, P65, CK 14) was performed. Samples were processed according to manufacturer´s instructions; information was analyzed with Stata 10 software. Results: A total of 1,922 invasive breast cancer cases were diagnosed from 2006 to 2008, 154 of which were triple-negative (ER negative, PR negative, HER-2 negative). Complete information was obtained in 84 of these cases: 50 cases (59.52%) were basal-like and 34 cases (40.48%) were non basal-like tumors. Conclusions: This study, the first in Colombia which seeks to determine through immunohistochemistry the prevalence of triple-negative basal-like breast cancer in the Colombian population, found said tumor prevalence to be at 8.01%, which is below that reported in worldwide literature (11.9%-25%).

Utilidad de marcadores inmunohistoquímicos para el diagnóstico de lesiones pigmentadas conjuntivales / Immunohistochemical markers in the diagnosis of pigmented conjunctival lesions

Objetivo/Método: Valorar la importancia de los marcadores inmunohistoquímicos para el diagnóstico de certeza de lesiones pigmentadas de la conjuntiva. Debido a la dificultad del diagnóstico clínico exacto, la sospecha de malignidad obliga a realizar una extirpación de la lesión y estudio anatomopatológico en el cual los marcadores inmunohistoquímicos ayudan a determinar la naturaleza de la lesión. Caso clínico/Discusión: Mujer de 25 años que presenta una lesión pigmentada en carúncula de aparición reciente y crecimiento rápido con aumento de la pigmentación. Se sospecha malignidad por lo que se realiza extirpación total de la lesión. El estudio microscópico muestra alteraciones celulares sugerentes de malignidad pero tras realizar marcadores inmunohistoquímicos el diagnóstico es nevus conjuntival compuesto(AU)

Objective/Method: The aim of this study was to assess the importance of immunohistochemical markers in the diagnosis of pigmented conjunctival lesions. Due to the difficulty of making an exact clinical diagnosis, the suspicion of malignancy requires the removal of the lesion and performing a histopathology study in which immunohistochemical markers may help to determine the nature of the lesion. Cases Report/Discussion: A case is presented of a 25 year-old woman with a pigmented lesion in the caruncle. It appeared recently and was growing fast with increasing pigmentation. Due to a suspicion of malignancy, the total lesion was removed. The microscopic study revealed cellular alterations which suggested malignancy. However, after carrying out immunohistochemical markers the diagnosis was conjunctival compound nevus(AU)

Canadian Association of Pathologists-Association canadienne des pathologistes National Standards Committee/Immunohistochemistry: best practice recommendations for standardization of immunohistochemistry tests.

Immunohistochemical and immunocytochemical assays are highly complex diagnostic analyses used to aid in the accurate identification and biologic characterization of tissue types in neoplastic and nonneoplastic diseases. Immunohistochemical tests are applied mainly to the diagnosis of neoplasms. Some immunohistochemical tests provide information of important prognostic and predictive value in selected human neoplasms and, as such, are often critical for the appropriate and effective treatment of patients. This document provides recommendations and opinions of the Canadian Association of Pathologists-Association canadienne des pathologistes National Standards Committee/Immunohistochemistry relevant to clinical immunohistochemical terminology, classification of immunohistochemical tests based on risk assessment, and quality control and quality assurance and summarizes matters to be considered for appropriate immunohistochemical/immunocytochemical test development, performance, and interpretation in diagnostic pathology and laboratory medicine.

Fibroxantoma atípico pigmentado o hemosiderótico / Pigmented or Hemosiderotic Atypical Fibroxanthoma

El fibroxantoma atípico pigmentado es una variante rara de fibroxantoma atípico caracterizada por áreas extensas de hemorragia, eritrofagocitosis y depósitos de hemosiderina en el citoplasma de las células neoplásicas. Afecta a pacientes de edad avanzada, y se manifiesta como nódulos cupuliformes o placas pigmentadas, de coloración heterogénea, en áreas de piel fotoexpuesta. Se presenta un caso de fibroxantoma atípico pigmentado de localización malar en un varón de 81 años de edad. Seis años después de la extirpación quirúrgica de la lesión, el paciente permanece en remisión completa, sin que se aprecien signos clínicos de persistencia tumoral o metástasis. Se revisan los 9 casos de fibroxantoma atípico pigmentado publicados en la literatura y se discuten las características histopatológicas y el diagnóstico diferencial de esta rara entidad (AU)

Pigmented atypical fibroxanthoma is a rare variant of atypical fibroxanthoma and is characterized by extensive areas of hemorrhage, erythrophagocytosis, and hemosiderin accumulation in the cytoplasm of the neoplastic cells. It affects elderly individuals and presents as irregularly pigmented, dome-shaped nodules or plaques on areas of skin exposed to the sun. We present a case of pigmented atypical fibroxanthoma on the cheek of an 81-year-old man. Six years after excision of the lesion, the patient remains in complete remission, with no signs of residual tumor or metastasis. The 9 cases of pigmented atypical fibroxanthoma reported in the literature are reviewed, and the histopathological features and differential diagnosis are discussed (AU)

Tumor de células granulares de piel mamaria. Estudio morfológico de dos casos mostrando inmunorreactividad frente alfa-inhibina / Granular cell tumor of the mammary skin. Morphological study of two cases showing immunoreactivity against alfa-inhibin

Introducción: El tumor de células granulares (TCG) es una lesión infrecuente en la mama, representando solo el 6-8 por ciento de los TCG, comprometiendo a menudo a la piel mamaria. Pacientes y métodos: Se revisa la casuística de TCG mamarios del Hospital Universitario La Fe de Valencia en un período de 19 años, con un total de 8000 especímenes biópsicos mamarios con 2200 diagnósticos de cáncer, realizando de forma retrospectiva un estudio morfológico (óptico, inmunohistoquímico y ultraestructural) a partir de material incluido en parafina. Resultados: Se detectan dos casos de TCG con afectación de piel mamaria con distinta presentación clínica (TCG como nódulo tumoral único y TCG como lesión tumoral múltiple en relación a una cicatriz de mastectomía previa). En ambas observaciones se comprobó, junto a otros datos ya conocidos (PAS + citoplásmica granular diastasa resistente, positividad a S-100, VT, CD68 y ultraestructura con numerosos cuerpos densos lisosomiales) la presencia de una reactividad inmunohistoquímica frente a alfa-inhibina. Conclusiones: Los TCG de glándula mamaria muestran reactividad inmunohistoquímica frente a alfa-inhibina, aspecto éste que amplia la aplicabilidad de este anticuerpo, sumándose al panel existente de inmunomarcadores en el diagnóstico de los TCG (AU)

Meningioma del surco olfatorio y poliposis nasosinusal. A propósito de un caso / Olfactory groove meningioma and nasosinusal polyposis. About a case

Presentamos el caso clínico de una mujer de 68 años diagnosticada por nuestro Servicio de Poliposis nasosinusal bilateral que presentaba Meningioma del Surco Olfatorio asociado. Tras la realización de TAC y RMN craneal, la paciente fue intervenida primero por el Servicio de Neurocirugía de nuestro hospital y tres años después practicamos Cirugía Endoscópica Nasosinusal Funcional (C.E.N.F.) sobre su poliposis. El seguimiento medio, por ORL y Neurocirugía, ha sido de 5 años; inicialmente presentó una fístula de LCR (no actualmente).En controles de imagen recientes se constató recidiva del meningioma con mejoría significativa de la permeabilidad nasal y, en menor grado, de su anosmia. Realizamos una revisión bibliográfica de esta patología poco frecuente en la literatura y que requiere un tratamiento quirúrgico en la mayoría de los casos (AU)

Infección por papiloma virus (HPV) en "carcinoma in situ" en un paciente con sida: a propósito de un caso clínico / HPV in "carcinoma in sito" associated with HIV/AIDS infection; a case report

La incidencia anual del condiloma acuminado es de un 106,5 por 100.000, es decir cerca del 0,1 por ciento en la población mundial. En individuos VIH+ la infección por HPV es más prevalente (20 por ciento en homosexuales VIH+ y 27 por ciento en SIDA). Los HPVDNA 11, 16, 18 y 31 son los tipos más comunes en condilomas anogenitales y en el 1 por ciento en lesiones premalignas y cáncer bucal. Objetivo: Nuestro propósito es presentar un paciente enfermo con SIDA, con condilomas múltiples en la mucosa bucal, y en uno de ellos un "carcinoma in situ", subyacente. Caso clínico: Paciente masculino de 46 años de edad condiagnóstico de SIDA debido a su historial clínico con mycobacteriosis atípica intestinal, candidiasis esofágica, y retinitis por citomegalovirus. Llegó a la consulta como paciente ambulatorio, buen estado general y bajo tratamiento antirretroviral de alta eficacia. A la exploración se encontraron condilomas múltiples esparcidos por toda la mucosa bucal. Se realizaron biopsias, histología e inmunohistoquímica, las cuales confirmaron infección por HPV. Se agregó el ensayo por PCR-FLP (Polimersa Chain Reaction-Restriction Fragment Length Polymorfismus) para obtener una tipificación sensible. En un condiloma de mucosa labial superior se diagnosticó un "carcinoma in situ". Los tipos de HPVDNA fueron 18 y 51.Se instaló terapia en tres etapas, aplicando láser de carbón-dioxide y exéresis quirúrgica con bisturí eléctrico. La zona del "carcinoma in situ" requirió una cirugía con margen de seguridad. Se pautó una terapia local y el seguimiento. Conclusión: No hemos encontrado ninguna publicación sobre "carcinoma in situ" bucal asociado al HPVDNA 18 y 51. La detección temprana de lesiones asociadas al HPV en lamucosa bucal es importante en la prevención del cáncer bucal (AU)

Papel del sistema de la hipocretina/orexina en la regulación del sueño / Role of the hipocretin/orexin system in sleep regulation

No disponible

Técnicas de desenmascaramiento antigénico e inmunohistoquímica. Estudio dirigido a anticuerpos con especiales dificultades de inmunodetección / Antigenic unmasking techniques in immunohistochemistry

No disponible

Valor diagnóstico de la proteína WT-1 como marcador inmunohistoquímico / Diagnostic value of the WT-1 protein as an inmunohistochemical marker

No disponible