Clinicopathological and Genomic Identification of Breast Cancers with No Impact on Mortality.

BACKGROUND: Implementing mammogram screening means that clinicians are seeing many breast cancers that will never develop metastases. The purpose of this study was to identify subgroups of breast cancer patients who did not present events related to long-term breast cancer mortality, taking into account diagnosis at breast screening, absence of palpability and axillary involvement, and genomic analysis with PAM50. PATIENTS AND METHODS: To identify them, a retrospective observational study was carried out selecting patients without any palpable tumor and without axillary involvement, and a genomic analysis was performed with PAM50. RESULTS: The probability of distant metastasis-free interval (DMFI) of 337 patients was 0.92 (95% CI, 0.90-0.93) at 20 years and 0.96 (95% CI, 0.92-1.00) in 95 patients (28%) with available PAM50 tests. In 22 (23.15%) luminal A tumors and in 9 (9.47%) luminal B tumors smaller than 1 cm, and in HER2 and basal type tumors, there were no metastatic events (20-year DMFI of 1.00). CONCLUSION: Patients with nonpalpable breast cancer found at screening with negative nodes are at very low risk. It is possible to identify subgroups without metastatic events by determining the intrinsic subtype and tumor size less than 1 cm. Therefore, de-escalation of treatment should be considered.

Pathogenic Variants Associated with Epigenetic Control and the NOTCH Pathway Are Frequent in Classic Hodgkin Lymphoma.

Classic Hodgkin lymphoma (cHL) constitutes a B-cell neoplasm derived from germinal center lymphocytes. Despite high cure rates (80-90%) obtained with the current multiagent protocols, a significant proportion of cHL patients experience recurrences, characterized by a lower sensitivity to second-line treatments. The genomic background of chemorefractory cHL is still poorly understood, limiting personalized treatment strategies based on molecular features. In this study, using a targeted next-generation sequencing (NGS) panel specifically designed for cHL research, we compared chemosensitive and chemorefractory diagnostic tissue samples of cHL patients. Furthermore, we longitudinally examined paired diagnosis-relapsesamples of chemorefractory cHL in order to define patterns of dynamic evolution and clonal selection. Pathogenic variants in NOTCH1 and NOTCH2 genes frequently arise in cHL. Mutations in genes associated with epigenetic regulation (CREBBP and EP300) are particularly frequent in relapsed/refractory cHL. The appearance of novel clones characterized by mutations previously not identified at diagnosis is a common feature in cHL cases showing chemoresistance to frontline treatments. Our results expand current molecular and pathogenic knowledge of cHL and support the performance of molecular studies in cHL prior to the initiation of first-line therapies.

Estudio de variantes genéticas en 169 pacientes de cáncer de pulmón no microcítico / Study of genetic variants in 169 non-small cell lung cancer patients

Introducción: El cáncer de pulmón es la principal causa de muerte por cáncer en nuestro país. El cáncer de pulmón de células no pequeñas (CPCNP) representa el paradigma de la medicina personalizada. El objetivo principal de este trabajo es estudiar la frecuencia en nuestro medio de las variantes clínicamente significativas más frecuentemente descritas en CPCNP. Material y métodos: Se estudia la expresión inmunohistoquímica de TTF1, p40 y PD-L1 y la frecuencia de variantes genéticas mediante secuenciación masiva (NGS) con un panel de 52 genes, en 174 muestras incluidas en parafina de CPNCP en 169 pacientes (111 hombres y 52 mujeres) de la provincia de Cádiz. Resultados: La expresión inmunohistoquímica de TTF1, p40 y PD-L1 fue positiva en el 87%, el 0% y el 46% de los adenocarcinomas y en el 0%, el 100% y el 41% de los carcinomas escamosos. En NGS, las variantes de un solo nucleótido (SNV) más frecuentes fueron KRAS (36%), EGFR (14%), BRAF (10%), PIK3CA (8%) y MET (3%). Las variantes en el número de copias (CNV) más frecuentes fueron las amplificaciones en NF1 (30%), EGFR (18%), CCND1 (9%), MYC (9%) y KRAS (7%). En mujeres, las SNV en EGFR fueron más frecuentes que en hombres (p<0,0001). El adenocarcinoma es el tipo histológico más frecuente con SNV en KRAS (p=0,007361) o en EGFR (p<0,0001). En 16 pacientes (9,47%) se detectaron fusiones génicas, 9 casos en el gen MET. Conclusiones: Detectamos nuevas asociaciones entre expresión inmunohistoquímica y algunas variantes génicas, que podrían tener impacto en el tratamiento de pacientes de CPNCP.(AU)

Introduction: Lung cancer is the leading cause of cancer death in our country. Non-small cell lung cancer (NSCLC) represents the paradigm of personalized medicine. The main objective of this study is analysing the distribution of the most frequently described clinically significant variants in NSCLC, in our environment. Material and methods: We studied the immunohistochemical expression of TTF1, p40 and PD-L1 and the genetic variants frequency using Next-Generation Sequencing (NGS) with a panel of 52 genes, in 174 NSCLC paraffin-embedded samples in 169 patients (111 men and 52 women) from the province of Cádiz. Results: The immunohistochemical expression of TTF1, p40 and PD-L1 was positive in 87%, 0% and 46% in adenocarcinoma, and 0%, 100% and 41% in squamous cell carcinoma. In NGS, the most common single nucleotide variants (SNVs) were KRAS (36%), EGFR (14%), BRAF (10%), PIK3CA (8%), and MET (3%). The most frequent copy number variants (CNVs) were amplifications in NF1 (30%), EGFR (18%), CCND1 (9%), MYC (9%) and KRAS (7%). In women, SNV in EGFR are more frequent than in men (P<.0001). Adenocarcinoma is the most frequent histological type with SNV in KRAS (P=.007361) or in EGFR (P<.0001). Gene fusions were detected in 16 patients (9.47%), in 9 cases in the MET gene. Conclusions: We detected associations, not described so far, between immunohistochemical expression and specific gene variants, which could have an impact on the treatment of NSCLC patients.(AU)

Whole slide imaging of tumour microenvironment in classical Hodgkin's lymphoma: development of a clinical prediction model based on programmed death-ligand 1 and tumorous Reed-Sternberg cells.

AIMS: The prognostic impact of programmed death-ligand 1 (PD-L1) cells in classic Hodgkin lymphoma (cHL) tumour microenvironment remains undefined. METHODS: Model development via Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines were followed. PD-L1+ and CD30+ tumoral Reed-Sternberg cells were quantified through whole slide imaging and digital image analysis in 155 digital histopathological slides of cHL. Univariate and multivariate survival analyses were performed. The analyses were reproduced for patients with advanced stages (IIB, III and IV) using the Advanced-stage cHL International Prognostic Index. RESULTS: The PD-L1/CD30 ratio was statistically significantly associated with survival outcomes. Patients with a PD-L1/CD30 ratio above 47.1 presented a shorter overall survival (mean OS: 53.7 months; 95% CI: 28.7 to 78.7) in comparison with patients below this threshold (mean OS: 105.4 months; 95% CI: 89.6 to 121.3) (p=0.04). When adjusted for covariates, the PD-L1/CD30 ratio retained prognostic impact, both for the OS (HR: 1.005; 95% CI: 1.002 to 1.008; p=0.000) and the progression-free survival (HR: 3.442; 95% CI: 1.045 to 11.340; p=0.04) in a clinical and histopathological multivariate model including the male sex (HR: 3.551; 95% CI: 0.986 to 12.786; p=0.05), a percentage of tumoral cells ≥10.1% (HR: 1.044; 95% CI: 1.003 to 1.087; p=0.03) and high risk International Prognostic Score (≥3 points) (HR: 6.453; 95% CI: 1.970 to 21.134; p=0.002). CONCLUSIONS: The PD-L1/CD30 ratio identifies a group of cHL patients with an increased risk of treatment failure. Its clinical application can be performed as it constitutes an easy to implement pathological information in the diagnostic work-up of patients with cHL.

[Study of genetic variants in 169 non-small cell lung cancer patients]. / Estudio de variantes genéticas en 169 pacientes de cáncer de pulmón no microcítico.

INTRODUCTION: Lung cancer is the leading cause of cancer death in our country. Non-small cell lung cancer (NSCLC) represents the paradigm of personalized medicine. The main objective of this study is analysing the distribution of the most frequently described clinically significant variants in NSCLC, in our environment. MATERIAL AND METHODS: We studied the immunohistochemical expression of TTF1, p40 and PD-L1 and the genetic variants frequency using Next-Generation Sequencing (NGS) with a panel of 52 genes, in 174 NSCLC paraffin-embedded samples in 169 patients (111 men and 52 women) from the province of Cádiz. RESULTS: The immunohistochemical expression of TTF1, p40 and PD-L1 was positive in 87%, 0% and 46% in adenocarcinoma, and 0%, 100% and 41% in squamous cell carcinoma. In NGS, the most common single nucleotide variants (SNVs) were KRAS (36%), EGFR (14%), BRAF (10%), PIK3CA (8%), and MET (3%). The most frequent copy number variants (CNVs) were amplifications in NF1 (30%), EGFR (18%), CCND1 (9%), MYC (9%) and KRAS (7%). In women, SNV in EGFR are more frequent than in men (P<.0001). Adenocarcinoma is the most frequent histological type with SNV in KRAS (P=.007361) or in EGFR (P<.0001). Gene fusions were detected in 16 patients (9.47%), in 9 cases in the MET gene. CONCLUSIONS: We detected associations, not described so far, between immunohistochemical expression and specific gene variants, which could have an impact on the treatment of NSCLC patients.

Identification of prognostic factors in classic Hodgkin lymphoma by integrating whole slide imaging and next generation sequencing.

Digital pathology and genomics are increasingly used to improve our understanding of lymphoid neoplasms. Algorithms for quantifying cell populations in the lymph node and genetics can be integrated to identify new biomarkers with prognostic impact in classic Hodgkin lymphoma (cHL). In 16 cHL patients, we have performed whole slide imaging (WSI) analysis and quantification of CD30+, CD20+, CD3+ and MUM1+ cells in whole tissue slides, and Next Generation Sequencing (NGS) in formalin fixed paraffin-embedded (FFPE) tissue, using a widely used NSG panel (Oncomine® Focus Assay) to define genetic variants underlying tumor development. The different cell populations could be successfully identified in scanned slides of cHL, supporting the inclusion of WSI in the histopathological evaluation of cHL as an adequate method for the quantification of different cell populations. We also performed genetic profiling in FFPE samples of cHL leading to the identification of copy number variations in the Neurofibromin 1 gene (17q11.2) and the Androgen Receptor gene (Xq12) accompanied by chromosomal gains and losses in CDK4, KRAS and FGFR2 genes. Progression-free survival (PFS) was statistically significantly higher in cHL patients with amplification in the NF1 gene combined with CD3+ cells above 28.6% (p = 0.006) and MUM1+ cells above 21.8% (p < 0.001). Moreover, patients with MUM1+ cells above 21.8% showed a statistically significantly higher PFS when combined with amplification of the AR gene (p < 0.001) and wild-type KRAS (p < 0.001). The integration of WSI analysis and DNA sequencing could be useful to improve our understanding of the biology of cHL and define risk subgroups.

Whole-slide image analysis identifies a high content of Hodgkin Reed-Sternberg cells and a low content of T lymphocytes in tumor microenvironment as predictors of adverse outcome in patients with classic Hodgkin lymphoma treated with ABVD.

Classic Hodgkin lymphoma (cHL) constitutes the most frequent lymphoma in young adults. Its histopathology is unique as a scattered tumor population, termed Hodgkin Reed-Sternberg (HRS) cells is diluted in a prominent tumor microenvironment (TME) composed of T lymphocytes, B lymphocytes, macrophages, neutrophils, eosinophils and histiocytes. Traditionally, the identification of prognostic biomarkers in the cHL TME has required visual inspection and manual counting by pathologists. The advent of whole-slide imaging (WSI) and digital image analysis methods could significantly contribute to improve this essential objective in cHL research, as a 10-20% of patients are still refractory or relapsed after conventional chemotherapy. In this work, we have digitized a total of 255 diagnostic cHL slides and quantified the proportion of HRS cells (CD30), B cells (CD20) and T cells (CD3) by digital image analysis. Data obtained where then correlated with the overall survival (OS) and progression free survival (PFS) of cHL patients. Quantification of HRS cells, B cells and T cells reflects the biological heterogeneity of the different cHL histological subtypes analyzed. A percentage of 2.00% of HRS cells statistically significantly discriminated between patients achieving a complete metabolic response (CMR) and refractory or relapsed (R/R) patients both for the OS (P=0.001) and PFS (P=0.005). Furthermore, patients with a percentage of T cells below the 26.70% in the TME showed a statistically significantly shorter OS (P=0.019) and PFS (P=0.041) in comparison with patients above this threshold. A subgroup of patients with a low content of T cells and high content of HRS cells exhibited a special aggressive clinical course. Currently, there is the need to implement quantitative and easy scalable methods to enhance clinical translation, as the cHL TME plays a central role in the clinical course of the disease. The results of this study could contribute to the identification of prognostic biomarkers specifically looking at the cHL TME and their inclusion in future clinical trials.

Características clínico-patológicas y supervivencia de pacientes con cáncer de mama de riesgo muy bajo / Clinicopathological characteristics and survival results of patients with ultralow risk breast cancer

Antecedentes y objetivo: La universalización del cribado mamográfico ha incrementado el diagnóstico de cánceres de mama con pronóstico excelente. La ausencia de tumor palpable les confiere un riesgo muy bajo de mortalidad por cáncer de mama. El objetivo del estudio fue identificar subgrupos con muy buena evolución a largo plazo.Pacientes y métodosIdentificamos pacientes con muy buena evolución mediante estudio descriptivo, observacional y retrospectivo. Los criterios de riesgo muy bajo fueron la procedencia del cribado mamográfico, sin tumor palpable, el fenotipo tumoral y la afectación ganglionar.ResultadosDe 746 pacientes con carcinoma de mama, con ganglios negativos, entre 2001 y 2015, 110 (14,75%) procedían del cribado con tumores no palpables. Ochenta y ocho (80%) eran hormonosensibles, 10 (9,10%) triples negativos y 11 (10%) HER2. La mediana de seguimiento fue 10 años (3,5-17). Solo tres pacientes desarrollaron metástasis, no hubo recidivas loco-regionales, siete presentaron segundos tumores primarios y hubo cuatro muertes, dos por cáncer de mama y dos por otras causas. El intervalo libre de metástasis a distancia (ILMD) fue 95,60% (intervalo de confianza (IC) 95% 90,70-100,50); 96,30% (IC 95% 91,21-99,39) en 88 tumores hormonosensibles, 100% en 34 hormonosensibles de grado histológico 1 (aproximación a luminales A) y 94,40% (IC 95% 86,76-102,04) en 54 de grado 2-3 (luminales B). En los triples negativos y HER2 fue 100%. En tumores menores y mayores de 1 cm fue 100% y 95,50% (IC 95% 89, 42-101,58).ConclusionesLas pacientes con tumores no palpables, detectados en el cribado mamográfico tienen un riesgo de recurrencia muy bajo. La buena evolución en los subgrupos luminal A, triple negativo, HER2 y menores de 1 cm puede explicar la eficacia del tratamiento, pero también los hace candidatos a desescalar su tratamiento. (AU)

Background and objective: To identify subgroups with good progress over an extended period, we used diagnostic screening, tumour palpability, tumour phenotype, and node involvement.Patients and methodsWe identified patients with good progress by means of a descriptive, observational and retrospective study.ResultsOf 746 patients diagnosed with node-negative breast cancer between 2001 and 2015: 110 (14.75%) had non-palpable screening-diagnosed tumours; 88 (80%) were endocrine-sensitive, 10 (9.10%) were triple-negative and 11 (10%) were HER2. Only 3 patients developed metastases, and there were 4 deaths: 2 from breast cancer and 2 from other causes. The distant recurrence-free interval (DRFI) was 95.60%: 100% in 34 endocrine-sensitive histological grade 1 (equivalent to luminal A) tumours, and 94.40% (95% CI 86.76–102.04) in 54 grade 2–3 (luminal B) tumours. In triple-negative and HER2 cases, it was 100%. In tumours <1 cm it was 100%, and >1 cm it was 95.50% (95% CI 79.42–100.98).ConclusionsPatients with non-palpable tumours detected by mammogram screening have ultralow risk. The good progress in the luminal A, triple-negative, HER2, and less than 1 cm subgroups may explain the efficacy of the treatment but it also makes them candidates to de-escalation of their treatment. (AU)

The Need for Standardization in Next-Generation Sequencing Studies for Classic Hodgkin Lymphoma: A Systematic Review.

Classic Hodgkin lymphoma (cHL) constitutes a B cell-derived neoplasm defined by a scarce tumoral population, termed Hodgkin and Reed-Sternberg (HRS) cells, submerged into a histologically heterogeneous microenvironment. The paucity of HRS cells has historically hampered genetic studies, rendering the identification of the recurrent genetic lesions and molecular pathways deregulated in this lymphoma difficult. The advent of high-throughput sequencing methods such as next-generation sequencing (NGS) could sensibly optimize the identification of the mutational landscape of cHL. However, there is no current consensus either in the design of panels for targeted NGS or in its most relevant clinical applications. In this work, we systematically review the current state of NGS studies of cHL, stressing the need for standardization both in the candidate genes to be analyzed and the bioinformatic pipelines. As different institutions have developed and implemented their own customized NGS-based protocols, to compare and systematically review the major findings of this ongoing research area could be of added value for centers that routinely perform diagnostic, monitoring and genotyping strategies in cHL samples. The results of this systematic review should contribute to the interdepartmental harmonization and achievement of a consensus in the current clinical applications of NGS studies of cHL.

Clinicopathological characteristics and survival results of patients with ultralow risk breast cancer. / Características clínico-patológicas y supervivencia de pacientes con cáncer de mama de riesgo muy bajo.

BACKGROUND AND OBJECTIVE: To identify subgroups with good progress over an extended period, we used diagnostic screening, tumour palpability, tumour phenotype, and node involvement. PATIENTS AND METHODS: We identified patients with good progress by means of a descriptive, observational and retrospective study. RESULTS: Of 746 patients diagnosed with node-negative breast cancer between 2001 and 2015: 110 (14.75%) had non-palpable screening-diagnosed tumours; 88 (80%) were endocrine-sensitive, 10 (9.10%) were triple-negative and 11 (10%) were HER2. Only 3 patients developed metastases, and there were 4 deaths: 2 from breast cancer and 2 from other causes. The distant recurrence-free interval (DRFI) was 95.60%: 100% in 34 endocrine-sensitive histological grade 1 (equivalent to luminal A) tumours, and 94.40% (95% CI 86.76-102.04) in 54 grade 2-3 (luminal B) tumours. In triple-negative and HER2 cases, it was 100%. In tumours <1 cm it was 100%, and >1 cm it was 95.50% (95% CI 79.42-100.98). CONCLUSIONS: Patients with non-palpable tumours detected by mammogram screening have ultralow risk. The good progress in the luminal A, triple-negative, HER2, and less than 1 cm subgroups may explain the efficacy of the treatment but it also makes them candidates to de-escalation of their treatment.

CD68 and CD83 immune populations in non-metastatic axillary lymph nodes are of prognostic value for the survival and relapse of breast cancer patients.

BACKGROUND: The foremost cause of death of breast cancer (BC) patients is metastasis, and the first site to which BC predominantly metastasizes is the axillary lymph node (ALN). Thus, ALN status is a key prognostic indicator at diagnosis. The immune system has an essential role in cancer progression and dissemination, so its evaluation in ALNs could have significant applications. In the present study we aimed to investigate the association of clinical-pathological and immune variables in the primary tumour and non-metastatic ALNs (ALNs-) of a cohort of luminal A and triple-negative BC (TNBC) patients with cancer-specific survival (CSS) and time to progression (TTP). METHODS: We analysed the differences in the variables between patients with different outcomes, created univariate and multivariate Cox regression models, validated them by bootstrapping and multiple imputation of missing data techniques, and used Kaplan-Meier survival curves for a 10-years follow-up. RESULTS: We found some clinical-pathological variables at diagnosis (tumour diameter, TNBC molecular profile and presence of ALN metastasis), and the levels of several immune markers in the two studied sites, to be associated with worse CSS and TTP. Nevertheless, only CD68 and CD83 in ALNs- were confirmed as independent prognostic factors for TTP. CONCLUSIONS: The study identified the importance of macrophage and dendritic cell markers as prognostic factors of relapse for BC. We highlight the importance of studying the immune response in ALNs-, which could be relevant to the prediction of BC patients' outcome.

Prognostic Role of the Expression of Latent-Membrane Protein 1 of Epstein-Barr Virus in Classical Hodgkin Lymphoma.

The prognostic impact of the presence of Epstein-Barr virus (EBV) in classical Hodgkin lymphoma (cHL) is controversial. Previous studies reported heterogeneous results, rendering difficult the clinical validation of EBV as a prognostic biomarker in this lymphoma. The objective of this study was to evaluate the survival impact of the expression of EBV Latent-Membrane Protein 1 (EBV-LMP1) in tumoral Hodgkin-Reed-Sternberg (HRS) cells of primary diagnostic samples of cHL. Formalin-Fixed Paraffin-Embedded (FFPE) lymph node samples from 88 patients with cHL were analyzed. Patients were treated with the standard first-line chemotherapy (CT) with Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) followed by radiotherapy. The Kaplan-Meier method and the Cox proportional hazards model were used for carrying out the survival analysis. In order to investigate whether the influence of EBV was age-dependent, analyses were performed both for patients of all ages and for age-stratified subgroups. In bivariate analysis, the expression of EBV was associated with older age (p = 0.011), mixed cellularity subtype cHL (p < 0.001) and high risk International Prognostic Score (IPS) (p = 0.023). Overall survival (OS) and progression-free survival (PFS) were associated with the presence of bulky disease (p = 0.009) and advanced disease at diagnosis (p = 0.016). EBV-positive cases did not present a significantly lower OS and PFS in comparison with EBV-negative cases, for all ages and when stratifying for age. When adjusted for covariates, absence of bulky disease at diagnosis (HR: 0.102, 95% CI: 0.02-0.48, p = 0.004) and limited disease stages (I-II) (HR: 0.074, 95% CI: 0.01-0.47, p = 0.006) were associated with a significant better OS. For PFS, limited-disease stages also retained prognostic impact in the multivariate Cox regression (HR: 0.145, 95% CI: 0.04-0.57, p = 0.006). These results are of importance as the early identification of prognostic biomarkers in cHL is critical for guiding and personalizing therapeutic decisions. The prognostic role of EBV in cHL could be modulated by the type of CT protocol employed and interact with the rest of presenting features.

Compositional and structural analysis of engineered stones and inorganic particles in silicotic nodules of exposed workers.

BACKGROUND: Engineered stone silicosis is an emerging disease in many countries worldwide produced by the inhalation of respirable dust of engineered stone. This silicosis has a high incidence among young workers, with a short latency period and greater aggressiveness than silicosis caused by natural materials. Although the silica content is very high and this is the key factor, it has been postulated that other constituents in engineered stones can influence the aggressiveness of the disease. Different samples of engineered stone countertops (fabricated by workers during the years prior to their diagnoses), as well as seven lung samples from exposed patients, were analyzed by multiple techniques. RESULTS: The different countertops were composed of SiO2 in percentages between 87.9 and 99.6%, with variable relationships of quartz and cristobalite depending on the sample. The most abundant metals were Al, Na, Fe, Ca and Ti. The most frequent volatile organic compounds were styrene, toluene and m-xylene, and among the polycyclic aromatic hydrocarbons, phenanthrene and naphthalene were detected in all samples. Patients were all males, between 26 and 46 years-old (average age: 36) at the moment of the diagnosis. They were exposed to the engineered stone an average time of 14 years. At diagnosis, only one patient had progressive massive fibrosis. After a follow-up period of 8 ± 3 years, four patients presented progressive massive fibrosis. Samples obtained from lung biopsies most frequently showed well or ill-defined nodules, composed of histiocytic cells and fibroblasts without central hyalinization. All tissue samples showed high proportion of Si and Al at the center of the nodules, becoming sparser at the periphery. Al to Si content ratios turned out to be higher than 1 in two of the studied cases. Correlation between Si and Al was very high (r = 0.93). CONCLUSION: Some of the volatile organic compounds, polycyclic aromatic hydrocarbons and metals detected in the studied countertop samples have been described as causative of lung inflammation and respiratory disease. Among inorganic constituents, aluminum has been a relevant component within the silicotic nodule, reaching atomic concentrations even higher than silicon in some cases. Such concentrations, both for silicon and aluminum showed a decreasing tendency from the center of the nodule towards its frontier.

Translational Applications of Artificial Intelligence and Machine Learning for Diagnostic Pathology in Lymphoid Neoplasms: A Comprehensive and Evolutive Analysis.

Genomic analysis and digitalization of medical records have led to a big data scenario within hematopathology. Artificial intelligence and machine learning tools are increasingly used to integrate clinical, histopathological, and genomic data in lymphoid neoplasms. In this study, we identified global trends, cognitive, and social framework of this field from 1990 to 2020. Metadata were obtained from the Clarivate Analytics Web of Science database in January 2021. A total of 525 documents were assessed by document type, research areas, source titles, organizations, and countries. SciMAT and VOSviewer package were used to perform scientific mapping analysis. Geographical distribution showed the USA and People's Republic of China as the most productive countries, reporting up to 190 (36.19%) of all documents. A third-degree polynomic equation predicts that future global production in this area will be three-fold the current number, near 2031. Thematically, current research is focused on the integration of digital image analysis and genomic sequencing in Non-Hodgkin lymphomas, prediction of chemotherapy response and validation of new prognostic models. These findings can serve pathology departments to depict future clinical and research avenues, but also, public institutions and administrations to promote synergies and optimize funding allocation.

Differences in the Immune Response of the Nonmetastatic Axillary Lymph Nodes between Triple-Negative and Luminal A Breast Cancer Surrogate Subtypes.

Breast cancer (BC) comprises four immunohistochemical surrogate subtypes of which triple-negative breast cancer (TNBC) has the highest risk of mortality. Axillary lymph nodes (ALNs) are the regions where BC cells first establish before distant metastasis, and the presence of tumor cells in the ALN causes an immune tolerance profile that contrasts with that of the nonmetastatic ALN (ALN-). However, few studies have compared the immune components of the ALNs- in BC subtypes. The present study aimed to determine whether differences between immune populations in the primary tumor and ALNs- were associated with the luminal A or TNBC subtype. We evaluated a retrospective cohort of 144 patients using paraffin-embedded biopsies. The TNBC samples tended to have a higher histologic grade and proliferation index and had higher levels of immune markers compared with luminal A in primary tumors and ALNs-. Two methods for validating the multivariate analysis found that histologic grade, intratumoral S100 dendritic cells, and CD8 T lymphocytes and CD57 natural killer cells in the ALNs- were factors associated with TNBC, whereas CD83 dendritic cells in the ALNs- were associated with the luminal A subtype. In conclusion, we found that intratumoral regions and ALNs- of TNBC contained higher concentrations of markers related to immune tolerance than luminal A. This finding partially explains the worse prognosis of patients with TNBC.

Peritumoral immune infiltrates in primary tumours are not associated with the presence of axillary lymph node metastasis in breast cancer: a retrospective cohort study.

BACKGROUND: The axillary lymph nodes (ALNs) in breast cancer patients are the body regions to where tumoral cells most often first disseminate. The tumour immune response is important for breast cancer patient outcome, and some studies have evaluated its involvement in ALN metastasis development. Most studies have focused on the intratumoral immune response, but very few have evaluated the peritumoral immune response. The aim of the present article is to evaluate the immune infiltrates of the peritumoral area and their association with the presence of ALN metastases. METHODS: The concentration of 11 immune markers in the peritumoral areas was studied in 149 patients diagnosed with invasive breast carcinoma of no special type (half of whom had ALN metastasis at diagnosis) using tissue microarrays, immunohistochemistry and digital image analysis procedures. The differences in the concentration of the immune response of peritumoral areas between patients diagnosed with and without metastasis in their ALNs were evaluated. A multivariate logistic regression model was developed to identify the clinical-pathological variables and the peritumoral immune markers independently associated with having or not having ALN metastases at diagnosis. RESULTS: No statistically significant differences were found in the concentrations of the 11 immune markers between patients diagnosed with or without ALN metastases. Patients with metastases in their ALNs had a higher histological grade, more lymphovascular and perineural invasion and larger-diameter tumours. The multivariate analysis, after validation by bootstrap simulation, revealed that only tumour diameter (OR = 1.04; 95% CI [1.00-1.07]; p = 0.026), lymphovascular invasion (OR = 25.42; 95% CI [9.57-67.55]; p < 0.001) and histological grades 2 (OR = 3.84; 95% CI [1.11-13.28]; p = 0.033) and 3 (OR = 5.18; 95% CI [1.40-19.17]; p = 0.014) were associated with the presence of ALN metastases at diagnosis. This study is one of the first to study the association of the peritumoral immune response with ALN metastasis. We did not find any association of peritumoral immune infiltrates with the presence of ALN metastasis. Nevertheless, this does not rule out the possibility that other peritumoral immune populations are associated with ALN metastasis. This matter needs to be examined in greater depth, broadening the types of peritumoral immune cells studied, and including new peritumoral areas, such as the germinal centres of the peritumoral tertiary lymphoid structures found in extensively infiltrated neoplastic lesions.

Data for glomeruli characterization in histopathological images.

The data presented in this article is part of the whole slide imaging (WSI) datasets generated in European project AIDPATH This data is also related to the research paper entitle "Glomerulosclerosis Identification in Whole Slide Images using Semantic Segmentation", published in Computer Methods and Programs in Biomedicine Journal [1]. In that article, different methods based on deep learning for glomeruli segmentation and their classification into normal and sclerotic glomerulous are presented and discussed. The raw data used is described and provided here. In addition, the detected glomeruli are also provided as individual image files. These data will encourage research on artificial intelligence (AI) methods, create and compare fresh algorithms, and measure their usability in quantitative nephropathology.

The Immune Response in Nonmetastatic Axillary Lymph Nodes Is Associated with the Presence of Axillary Metastasis and Breast Cancer Patient Outcome.

Tumor cells can modify the immune response in primary tumors and in the axillary lymph nodes with metastasis (ALN+) in breast cancer (BC), influencing patient outcome. We investigated whether patterns of immune cells in the primary tumor and in the axillary lymph nodes without metastasis (ALN-) differed between patients diagnosed without ALN+ (diagnosed-ALN-) and with ALN+ (diagnosed-ALN+) and the implications for clinical outcome. Eleven immune markers were studied using immunohistochemistry, tissue microarray, and digital image analysis in 141 BC patient samples (75 diagnosed-ALN+ and 66 diagnosed-ALN-). Two logistic regression models were derived to identify the clinical, pathologic, and immunologic variables associated with the presence of ALN+ at diagnosis. There are immune patterns in the ALN- associated with the presence of ALN+ at diagnosis. The regression models revealed a small subgroup of diagnosed-ALN+ with ALN- immune patterns that were more similar to those of the ALN- of the diagnosed-ALN-. This small subgroup also showed similar clinical behavior to that of the diagnosed-ALN-. Another small subgroup of diagnosed-ALN- with ALN- immune patterns was found whose members were more similar to those of the ALN- of the diagnosed-ALN+. This small subgroup had similar clinical behavior to the diagnosed-ALN+. These data suggest that the immune response present in ALN- at diagnosis could influence the clinical outcome of BC patients.

Inteligencia artificial en Anatomía Patológica / Artificial intelligence in Pathological Anatomy

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Immune response profile of primary tumour, sentinel and non-sentinel axillary lymph nodes related to metastasis in breast cancer: an immunohistochemical point of view.

Approximately 1.67 million new cases of breast cancer (BC) are diagnosed annually, and patient survival significantly decreases when the disease metastasizes. The axillary lymph nodes (ALNs) are the main doorway for BC tumoral cell escape, through which cells can disseminate to distant organs. The immune response, which principally develops in the lymph nodes, is linked to cancer progression, and its efficacy at controlling tumoral growth is compromised during the disease. Immunohistochemistry (IHC) is one of the most widely used research techniques for studying the immune response. It allows the measurement of the expression of particular markers related to the immune populations. This review focuses on the role of the immune populations in the primary tumour in the locoregional metastasis of the ALN, and the relationship of the immune response in these regions to distant metastasis. We considered only studies of immune cells using IHC techniques. In particular, lymphocytes, macrophages and dendritic cells all play important roles in BC and have been extensively studied. Although further research is needed, there is much evidence of their role in the invasion of the ALN and distant organs. Their association with tumoral growth or protection has not yet been demonstrated decisively and is very likely to be determined by a combination of factors. Moreover, even though IHC is a widely used technique in cancer diagnosis and research, there is still room for improvement, since its quantification needs to be properly standardized.