RANK in cancer-associated fibroblasts: A valuable prognostic determinant for metastasis in early-stage breast cancer patients.

BACKGROUND: The molecular system of receptor activator of nuclear factor kappa-ß (RANK) and its ligand (RANKL) plays a role in a variety of physiological and pathological processes. These encompass the regulation of bone metabolism, mammary gland development, immune function, as well as their involvement and tumorigenesis. Nevertheless, limited knowledge exists regarding their function within the tumor microenvironment. METHODS AND RESULTS: We explored the significance of RANK expression in cancer-associated fibroblasts (CAFs) as a prognostic biomarker in early breast cancer patients (BCPs) by immunohistochemistry. Results reveal a significant correlation between high RANK expression in CAFs and an increased risk of metastasis (p= 0.006), shorter metastasis-free survival (MFS) [p= 0.007, OR (95%CI) = 2.290 (1.259-4.156)], and lower overall survival (OS) [p= 0.004, OR (95%CI) = 2.469 (1.343-4.541)]. Upon analyzing the phenotype of CD34(-) CAFs isolated from primary tumors in BCPs, we observed co-expression of RANK with CD105 marker by immunofluorescence and flow cytometry, characteristic of mesenchymal stem/stromal cells (MSCs), suggesting the possible cellular origin. Also RANKL-RANK system increase the OCT-4, SOX-2 and DKK-1 (dickkopf 1) gene expression in CD34(-) CAFs by RT-PCR. Moreover, this system plays a crucial role in the migration of these CD34(-) CAFs. CONCLUSIONS: These results support the clinical relevance of RANK in CAFs and propose its potential as a future therapeutic target in the treatment of early BCPs.

CD105 expression in cancer-associated fibroblasts: a biomarker for bone metastasis in early invasive ductal breast cancer patients.

Introduction: Bone metastasis is one of the causes that mainly decrease survival in patients with advanced breast cancer. Therefore, it is essential to find prognostic markers for the occurrence of this type of metastasis during the early stage of the disease. Currently, cancer-associated fibroblasts, which represent 80% of the fibroblasts present in the tumor microenvironment, are an interesting target for studying new biomarkers and developing alternative therapies. This study evaluated the prognostic significance of the CD105 expression in cancer-associated fibroblasts in early breast cancer patients. Methods: Immunohistochemistry was used to assess CD105 expression in invasive ductal breast carcinomas (n = 342), analyzing its association with clinical and pathological characteristics. Results: High CD105 expression in cancer-associated fibroblasts was associated with an increased risk of metastatic occurrence (p = 0.0003), particularly bone metastasis (p = 0.0005). Furthermore, high CD105 expression was associated with shorter metastasis-free survival, bone metastasis-free survival, and overall survival (p = 0.0002, 0.0006, and 0.0002, respectively). CD105 expression also constituted an independent prognostic factor for metastasis-free survival, bone metastasis-free survival, and overall survival (p = 0.0003, 0.0006, and 0.0001, respectively). Discussion: The high CD105 expression in cancer-associated fibroblasts is an independent prognostic marker for bone metastasis in early breast cancer patients. Therefore, the evaluation of CD105(+) CAFs could be crucial to stratify BCPs based on their individual risk profile for the development of BM, enhancing treatment strategies and outcomes.

Multicenter study of diffuse pleural mesothelioma. histopathological and immunohistochemical features / Estudio multicéntrico de características histopatológicas e inmunohistoquímicas del mesotelioma pleural difuso

Abstract The pathological diagnosis of diffuse pleural mesothelioma (DPM) contributes to treatment selection and clinical trials interpretation. To know its characteristics and evaluate the viability of comprehensive pathological diagnosis of DPM in Argentina we did a retrospective descriptive study of DPM cases reported from 2009 to 2018. We analyzed 398 cases corresponding to 238 (60%) men and 160 (40%) women, median age 66 years, from surgical biopsies (78%), small biopsies (16.5%) and surgical resections (5.5%). The 77% were epithelioid (E-DPM), 12% biphasic, 10% sarcomatoid, and 4 cases transitional variant. In E-DPM the main pattern was tubular in 36% and solid in 33%. There was a second pattern in 179 cases. Considering the main pattern and the second together, 48% presented tubular subtype and 48% solid subtype. Stroma, necrosis, and nuclear score showed significant differences between E-DPM and non-epithelioid mesotheliomas. Overall tumor grade was predominantly low in E-DPM, except for 42% of the solid main pattern. We recognized the transitional variant extensively in 4 cases and focally in 8. The immunohistochemical antibody panel used included pan-cytokeratin, calretinin, WT-1, cytokeratin 5, CEA and TTF-1. The expression of cytokeratin 5, calretinin and WT-1 was lower in the sarcomatoid type (43%, 87 and 37%) than in the epithelioid type (92%, 98% and 93%). This study highlights the tumor heterogeneity of DPM that shows the diagnostic difficulty, and the feasibility of evaluating histological aggressiveness in E-DPM, B-DPM and S-DPM in our country.

Resumen El diagnóstico patológico del mesotelioma pleural difuso (MPD) contribuye a la selección del tratamiento y a la interpretación de los ensayos clínicos. Para conocer sus características y evaluar la viabilidad del diagnóstico patológico de MPD en Argentina se realizó un estudio descriptivo retros pectivo de los casos de MPD informados de 2009 a 2018. Se analizaron 398 casos correspondientes a 238 (60%) hombres y 160 (40%) mujeres, mediana de edad de 66 años, a partir de biopsias quirúrgicas (78%), biopsias pequeñas (16.5%) y resecciones quirúrgicas (5.5%). El 77% fue epitelioide (E-MPD), 12% bifásicos, 10% sarcomatoides y 4 casos variante transicional. En E-MPD se encontró como patrón principal el tubular en 36% y el sólido en 33%. Hubo un segundo patrón en 179 casos. Considerando el principal y el segundo patrón en conjunto, el 48% presentó subtipo tubular y el 48% subtipo sólido. El estroma, la necrosis y el score nuclear mostraron diferencias significativas entre E-MPD y mesoteliomas no epitelioides. El grado general del tumor fue predominantemente bajo en E-MPD, a excepción del 42% del patrón principal sólido. Reconocimos la variante transicional en forma extensa en 4 casos y focalmente en 8. La expresión de citoqueratina 5, calretinina y WT-1 fue menor en el tipo sarcomatoide (43%, 87 y 37%) que en el tipo epitelioide (92%, 98% y 93%). Este estudio destaca la heterogeneidad tumoral de MPD que evidencia la dificu ltad en el diagnóstico y la viabilidad de evaluar la agresividad histológica en E-MPD, B-MPD y S-MPD en nuestro país.

Multicenter study of diffuse pleural mesothelioma. Histopathological and immunohistochemical features.

The pathological diagnosis of diffuse pleural mesothelioma (DPM) contributes to treatment selection and clinical trials interpretation. To know its characteristics and evaluate the viability of comprehensive pathological diagnosis of DPM in Argentina we did a retrospective descriptive study of DPM cases reported from 2009 to 2018. We analyzed 398 cases corresponding to 238 (60%) men and 160 (40%) women, median age 66 years, from surgical biopsies (78%), small biopsies (16.5%) and surgical resections (5.5%). The 77% were epithelioid (E-DPM), 12% biphasic, 10% sarcomatoid, and 4 cases transitional variant. In E-DPM the main pattern was tubular in 36% and solid in 33%. There was a second pattern in 179 cases. Considering the main pattern and the second together, 48% presented tubular subtype and 48% solid subtype. Stroma, necrosis, and nuclear score showed significant differences between E-DPM and non-epithelioid mesotheliomas. Overall tumor grade was predominantly low in E-DPM, except for 42% of the solid main pattern. We recognized the transitional variant extensively in 4 cases and focally in 8. The immunohistochemical antibody panel used included pan-cytokeratin, calretinin, WT-1, cytokeratin 5, CEA and TTF-1. The expression of cytokeratin 5, calretinin and WT-1 was lower in the sarcomatoid type (43%, 87 and 37%) than in the epithelioid type (92%, 98% and 93%). This study highlights the tumor heterogeneity of DPM that shows the diagnostic difficulty, and the feasibility of evaluating histological aggressiveness in E-DPM, B-DPM and S-DPM in our country.

El diagnóstico patológico del mesotelioma pleural difuso (MPD) contribuye a la selección del tratamiento y a la interpretación de los ensayos clínicos. Para conocer sus características y evaluar la viabilidad del diagnóstico patológico de MPD en Argentina se realizó un estudio descriptivo retrospectivo de los casos de MPD informados de 2009 a 2018. Se analizaron 398 casos correspondientes a 238 (60%) hombres y 160 (40%) mujeres, mediana de edad de 66 años, a partir de biopsias quirúrgicas (78%), biopsias pequeñas (16.5%) y resecciones quirúrgicas (5.5%). El 77% fue epitelioide (E-MPD), 12% bifásicos, 10% sarcomatoides y 4 casos variante transicional. En E-MPD se encontró como patrón principal el tubular en 36% y el sólido en 33%. Hubo un segundo patrón en 179 casos. Considerando el principal y el segundo patrón en conjunto, el 48% presentó subtipo tubular y el 48% subtipo sólido. El estroma, la necrosis y el score nuclear mostraron diferencias significativas entre E-MPD y mesoteliomas no epitelioides. El grado general del tumor fue predominantemente bajo en E-MPD, a excepción del 42% del patrón principal sólido. Reconocimos la variante transicional en forma extensa en 4 casos y focalmente en 8. La expresión de citoqueratina 5, calretinina y WT-1 fue menor en el tipo sarcomatoide (43%, 87 y 37%) que en el tipo epitelioide (92%, 98% y 93%). Este estudio destaca la heterogeneidad tumoral de MPD que evidencia la dificu ltad en el diagnóstico y la viabilidad de evaluar la agresividad histológica en E-MPD, B-MPD y S-MPD en nuestro país.

[Histopathology and molecular profile of a case of prostatic Ewing sarcoma]. / Histopatología y perfil molecular de un caso de sarcoma de Ewing prostático.

We report a case of Ewing sarcoma localized in the prostate gland of a 33-year-old patient without bone or soft tissue involvement. Evidence of EWS and FLI1 gene translocation was detected by fluorescence in situ hybridization (FISH). This is an unusual case with an interesting clinical presentation; indeed, only a few cases have been reported to date and not all have the supporting biological studies now considered essential for the diagnosis.