[Cystic tubulopapillary adenoma with apocrine differentiation and BRAF V600E mutation. A case report and review of the literature]. / Adenoma tubulopapilar quístico con diferenciación apocrina: descripción de un caso con mutación de BRAF V600E y revisión de la literatura.

Syringocystadenoma papilliferum (SCAP), tubular adenoma (TA) and hydrocystoma (HC) are benign adnexal tumors. Recently it has been suggested that these lesions belong to the same morphological spectrum: Tubulopapillary cystic adenoma with apocrine differentiation (TPCAa). BRAF and K-Ras (KRAS) mutations have been described in SCAP and TA, but not in HC. Moreover, verrucous epithelial proliferations have been observed in TPCAa. We present a case of TPCAa with BRAF V600E mutation and BRAF VE1 immunohistochemical expression in the SCAP, AT, HC and verrucous hyperplasia components.

Carcinoma de células renales asociado a amplificación del gen TFEB. Presentación de un caso y revisión de la literatura / TFEB-amplified renal cell carcinoma. A case report and review of the literature

Los carcinomas renales asociados a translocación de factores de transcripción de la familia MiT/TFE incluyen, según la última clasificación de la Organización Mundial de la Salud, carcinomas con translocación Xp11 que involucran al gen TFE3 y carcinomas con translocación t(6;11)(p21;q12) que afectan al gen TFEB. Cada uno de estos subtipos presenta características clinicopatológicas y moleculares bien definidas. Actualmente, con el desarrollo de las técnicas moleculares se han descrito neoplasias con sustento molecular en estos mismos genes, pero con alteraciones distintas a la translocación. En este sentido, recientemente se han publicado carcinomas renales asociados a amplificación de TFEB que presentan diferencias pronósticas a los casos asociados a translocación y que podrían, por tanto, constituir una nueva entidad. Nosotros presentamos un caso de carcinoma renal asociado a amplificación de TFEB, describimos sus características clinicopatológicas y hacemos una revisión actualizada sobre estas neoplasias

Renal carcinomas associated with translocation of transcription factors of the MiT/TFE family include, according to the latest World Health Organization classification, carcinomas with Xp11 translocation that involve the TFE3 gene and those with translocation t(6;11)(p21;q12) that affect the TFEB gene. Each one of these sub-types have well-defined clinicopathological and molecular characteristics. Currently, progress in molecular techniques has led to the description of neoplasms with molecular changes in these same genes but with alterations different to translocation. Thus, recently, cases have been published of TFEB-amplified renal carcinomas with prognoses that vary from cases associated with translocation and could therefore represent a new entity. We present a case of TFEB-amplified renal carcinoma with a full description of the clinicopathological characteristics and an updated revision of these neoplasms

[TFEB-amplified renal cell carcinoma. A case report and review of the literature]. / Carcinoma de células renales asociado a amplificación del gen TFEB. Presentación de un caso y revisión de la literatura.

Renal carcinomas associated with translocation of transcription factors of the MiT/TFE family include, according to the latest World Health Organization classification, carcinomas with Xp11 translocation that involve the TFE3 gene and those with translocation t(6;11)(p21;q12) that affect the TFEB gene. Each one of these sub-types have well-defined clinicopathological and molecular characteristics. Currently, progress in molecular techniques has led to the description of neoplasms with molecular changes in these same genes but with alterations different to translocation. Thus, recently, cases have been published of TFEB-amplified renal carcinomas with prognoses that vary from cases associated with translocation and could therefore represent a new entity. We present a case of TFEB-amplified renal carcinoma with a full description of the clinicopathological characteristics and an updated revision of these neoplasms.

Liposarcoma pleomórfico: estudio molecular de un caso y revisión bibliográfica / Pleomorphic liposarcoma: molecular study of one case and bibliographic review

El liposarcoma pleomórfico es un sarcoma de alto grado que ocurre generalmente en la sexta-séptima décadas de la vida, afecta principalmente a partes blandas profundas de las extremidades inferiores y muestra una amplia variedad de patrones morfológicos, por lo que puede confundirse con otras lesiones tanto adipocíticas como no adipocíticas. La identificación definitiva de lipoblastos pleomórficos, que pueden ser muy escasos, es un requisito indispensable para el diagnóstico, por lo que es recomendable un muestreo amplio del tumor (AU)

Pleomorphic liposarcoma is a high grade sarcoma occurring generally in the sixth to seventh decades of life and mainly affects the deep soft tissue of the lower extremities. As it can show a wide variety of morphologic patterns, it may be confused with other adipocytic and non adipocytic lesions. Definitive identification of pleomorphic lipoblasts is indispensable for diagnosis; however, as they can be very scarce, extensive sampling of the tumor is recommended (AU)

[From tumour to tumour: Metastasis of invasive ductal breast carcinoma to chromophobe renal cell carcinoma]. / Tumor a tumor: metástasis de carcinoma ductal infiltrante de mama sobre carcinoma de células cromófobas de riñón.

The coexistence of two or more tumours in the same patient is unusual, but even rarer is the metastasis of one tumour to another. Most reports are based on evidence from autopsies; very few refer to surgical specimens. The most common primary tumour is pulmonary carcinoma and most frequent metastatic tumour is renal clear cell carcinoma. We present the case of a 54 year-old female with a past history of infiltrating ductal carcinoma of the breast with metastases in lung, lymph nodes and bone. Three months previously to her referral to us, she had developed a renal mass and underwent nephrectomy. Histopathology revealed a renal chromophobe cell carcinoma with intratumoral breast cancer metastasis. We describe the histopathological, immunohistochemical and molecular features and review the recent literature.

Tumor a tumor: metástasis de carcinoma ductal infiltrante de mama sobre carcinoma de células cromófobas de riñón / From tumour to tumour: metastasis of invasive ductal breast carcinoma to chromophobe renal cell carcinoma

La coexistencia de 2 o más tumores en un paciente es un hecho poco frecuente y más infrecuentes son las metástasis de tumor a tumor. La mayoría de las publicaciones incluyen hallazgos autópsicos y, en menor número, hallazgos en piezas quirúrgicas-biopsias. El origen primario más frecuente es el carcinoma de pulmón, siendo el receptor más frecuente el carcinoma de células claras renal. Describimos el caso de una paciente de 54años con historia remota de carcinoma ductal infiltrante de mama derecha, que presentó en el transcurso afectación metastásica a nivel pulmonar, ganglionar, óseo y hace 3 meses una lesión en riñón derecho. Se sometió a nefrectomía. El estudio anatomopatológico reveló un carcinoma renal de células cromófobas con metástasis intratumoral de carcinoma ductal infiltrante de mama. Se describen los hallazgos histológicos, inmunohistoquímicos y moleculares, con revisión de la literatura reciente (AU)

The coexistence of two or more tumours in the same patient is unusual, but even rarer is the metastasis of one tumour to another. Most reports are based on evidence from autopsies; very few refer to surgical specimens. The most common primary tumour is pulmonary carcinoma and most frequent metastatic tumour is renal clear cell carcinoma. We present the case of a 54 year-old female with a past history of infiltrating ductal carcinoma of the breast with metastases in lung, lymph nodes and bone. Three months previously to her referral to us, she had developed a renal mass and underwent nephrectomy. Histopathology revealed a renal chromophobe cell carcinoma with intratumoral breast cancer metastasis. We describe the histopathological, immunohistochemical and molecular features and review the recent literature (AU)

Mutación de BRAFV600E en restos nefrogénicos perilobares hiperplásicos activos asociados a adenoma metanéfrico / BRAFV600E mutation in active hyperplastic perilobar nephrogenic rests associated with metanephric adenoma

La cascada de señalización intracelular RAS/RAF/MEK/ERK es una de las vías moleculares más frecuentes en la oncogénesis, actuando fundamentalmente a través de mutaciones somáticas. La mutación conductora de BRAFV600E se ha descrito entre otros en melanoma, carcinoma colorrectal, carcinoma pulmonar y carcinoma papilar de tiroides. En el 90% de los adenomas metanéfricos se encuentra presente dicha mutación. Se ha sugerido que el desarrollo de estos tumores podría estar ligado al túbulo proximal del riñón fetal o a restos nefrogénicos, los cuales son supuestos precursores del tumor de Wilms. En este artículo breve presentamos un caso de restos nefrogénicos perilobares hiperplásicos activos asociados a un adenoma metanéfrico mostrando ambas lesiones la mutación BRAFV600E estudiada por reacción en cadena de la polimerasa (AU)

The RAS/RAF/MEK/ERK intracellular signaling cascade is one of the most ubiquitous molecular pathways through which human neoplasms arise. Alterations in BRAFV600E work as well-recognized oncogenic driver mutations in melanoma, colorectal, lung and thyroid papillary carcinoma. BRAFV600E mutations have also been reported in the 90% of metanephric adenomas. It has been suggested that the development of the latter could be related to the developing proximal tubule of the foetal kidney or nephrogenic rests, which are supposed to be putative precursors of Wilms tumour. We report a case of synchronous active hyperplastic perilobar nephrogenic rests and metanephric adenoma harbouring a BRAFV600E mutation confirmed by polymerase chain reaction (AU)

Duodenal Ewing’s sarcoma: unusual location and atypical EWRS-1 translocation / Sarcoma de Ewing duodenal: localización inusual y traslocación atípica EWRS-1

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The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis.

Melanoma is a highly metastatic and malignant skin cancer having poor rates of patient survival. Since the incidence of melanoma is steadily increasing in the population, finding prognostic and therapeutic targets are crucial tasks in cancer. The dioxin receptor (AhR) is required for xenobiotic-induced toxicity and carcinogenesis and for cell physiology and organ homeostasis. Yet, the mechanisms by which AhR affects tumor growth and dissemination are largely uncharacterized. We report here that AhR contributes to the tumor-stroma interaction, blocking melanoma growth and metastasis when expressed in the tumor cell but supporting melanoma when expressed in the stroma. B16F10 cells engineered to lack AhR (small hairpin RNA for AhR) exacerbated melanoma primary tumorigenesis and lung metastasis when injected in AhR+/+ recipient mice but not when injected in AhR- /- mice or when co-injected with AhR-/- fibroblasts in an AhR+/+ stroma. Contrary, B16F10 cells expressing a constitutively active AhR had reduced tumorigenicity and invasiveness in either AhR genetic background. The tumor suppressor role of AhR in melanoma cells correlated with reduced migration and invasion, with lower numbers of cancer stem-like cells and with altered levels of ß1-integrin and caveolin1. Human melanoma cell lines with highest AHR expression also had lowest migration and invasion. Moreover, AHR expression was reduced in human melanomas with respect to nevi lesions. We conclude that AhR knockdown in melanoma cells requires stromal AhR for maximal tumor progression and metastasis. Thus, AhR can be a molecular marker in melanoma and its activity in both tumor and stromal compartments should be considered.

Fitting a xenobiotic receptor into cell homeostasis: how the dioxin receptor interacts with TGFbeta signaling.

As our knowledge on the mechanisms that control cell function increases, more complex signaling pathways and quite intricate cross-talks among regulatory proteins are discovered. Establishing accurate interactions between cellular networks is essential for a healthy cell and different alterations in signaling are known to underline human disease. Transforming growth factor beta (TGFbeta) is an extracellular cytokine that regulates such critical cellular responses as proliferation, apoptosis, differentiation, angiogenesis and migration, and it is assumed that the latency-associated protein LTBP-1 plays a relevant role in TGFbeta targeting and activation in the extracellular matrix (ECM). The dioxin receptor (AhR) is a unique intracellular protein long studied because of its critical role in xenobiotic-induced toxicity and carcinogenesis. Yet, a large set of studies performed in cellular systems and in vivo animal models have suggested important xenobiotic-independent functions for AhR in cell proliferation, differentiation and migration and in tissue homeostasis. Remarkably, AhR activity converges with TGFbeta-dependent signaling through LTBP-1 since cells lacking AhR expression have phenotypic alterations that can be explained, at least in part, by the coordinated regulation of both proteins. Here, we will discuss the existence of functional interactions between AhR and TGFbeta signaling. We will focus on regulatory and functional aspects by analyzing how AhR status determines TGFbeta activity and by proposing a mechanism through which LTBP-1, a novel AhR target gene, mediates such effects. We will integrate ECM proteases in the AhR-LTBP-1-TGFbeta axis and suggest a model that could help explain some in vivo phenotypes associated to AhR deficiency.

Recruitment of CREB1 and histone deacetylase 2 (HDAC2) to the mouse Ltbp-1 promoter regulates its constitutive expression in a dioxin receptor-dependent manner.

Latent TGFbeta-binding protein 1 (LTBP-1) is a key regulator of TGFbeta targeting and activation in the extracellular matrix. LTBP-1 is recognized as a major docking molecule to localize, and possibly to activate, TGFbeta in the extracellular matrix. Despite this relevant function, the molecular mechanisms regulating Ltbp-1 transcription remain largely unknown. Previous results from our laboratory revealed that mouse embryonic fibroblasts (MEF) lacking dioxin receptor (AhR) had increased Ltbp-1 mRNA expression and elevated TGFbeta activity, suggesting that AhR repressed Ltbp-1 transcription. Here, we have cloned the mouse Ltbp-1 gene promoter and analysed its mechanism of transcriptional repression by AhR. Reporter gene assays, AhR over-expression and site-directed mutagenesis showed that basal Ltbp-1 transcription is AhR-dependent. Chromatin immunoprecipitation (ChIP) and RNA interference (RNAi) revealed that AhR regulates Ltbp-1 transcription by a mechanism involving recruitment of co-activators such as CREB1 and co-repressors such as HDAC2 to the Ltbp-1 promoter. In AhR-expressing (AhR+/+) MEF cells, the recruitment of HDAC1, 2 and 4 correlated with decreased K8H4 acetylation and impaired binding of pCREB(Ser133) to the Ltbp-1 promoter, likely maintaining a constitutive repressed state. AhR-/- MEF cells had the opposite pattern of HDACs and pCREB1(Ser133) binding to Ltbp-1 promoter, and therefore, over-expressed Ltbp-1 mRNA. In agreement, siRNA for HDAC2 increased Ltbp-1 expression and K8H4 acetylation in AhR+/+ but not in AhR-/- MEF cells. We suggest that HDAC2 binding keeps Ltbp-1 promoter repressed in AhR+/+ MEF cells, whereas in AhR-null MEF cells the absence of HDAC2 and the binding of pCREB(Ser133) allow Ltbp-1 transcription. Thus, epigenetics can contribute to constitutive Ltbp-1 repression by a mechanism requiring AhR activity.

LTBP-1 blockade in dioxin receptor-null mouse embryo fibroblasts decreases TGF-beta activity: Role of extracellular proteases plasmin and elastase.

In mouse embryonic fibroblasts (MEF) lacking dioxin receptor (AhR), high levels of latent transforming growth factor-beta (TGF-beta)-binding protein-1 (LTBP-1) correlated with increased TGF-beta1 activity, an observation suggesting that LTBP-1 could contribute to maintain TGF-beta1 levels. Here, using small interfering RNAs (siRNA), we have first analyzed if LTBP-1 expression affected TGF-beta1 activity in MEF cells. We have then determined how LTBP-1 levels could alter the activity of extracellular proteases known to activate TGF-beta1, and finally, whether protease inhibition could reduce TGF-beta1 activation. LTBP-1 inhibition by siRNA in AhR-/- MEF decreased the amount of active TGF-beta1 and reduced plasminogen activators (PA)/plasmin and elastase activities and thrombospondin-1 (TSP-1) expression, without significantly affecting their mRNA levels. On the contrary, LTBP-1 siRNA restored matrix metalloproteinase-2 (MMP-2) activity in AhR-/- MEF. Interestingly, whereas a TGF-beta1 neutralizing antibody mimicked many of the LTBP-1 siRNA effects on extracellular proteases, addition of recombinant TGF-beta1 protein increased proteases activity over basal levels in AhR-/- MEF. These proteases contributed to TGF-beta activation since their specific inhibitors reduced active TGF-beta levels in these cells. These results suggest that LTBP-1 contributes to TGF-beta1 activation in MEF, possibly by influencing the activities of PA/plasmin, elastase, TSP-1, and MMP-2. TGF-beta1, on the other hand, could be also involved in maintaining the activity of these extracellular proteases. Thus, LTBP-1 appears to play a role in TGF-beta1 activation through a process involving extracellular protease activities, which, in turn, could be affected by TGF-beta1 levels.