ETV6::NTRK3 Fusion-Positive Wild-Type Gastrointestinal Stromal Tumor (GIST) with Abundant Lymphoid Infiltration (TILs and Tertiary Lymphoid Structures): A Report on a New Case with Therapeutic Implications and a Literature Review.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with proto-oncogene, receptor tyrosine kinase (c-kit), or PDGFRα mutations detected in around 85% of cases. GISTs without c-kit or platelet-derived growth factor receptor alpha (PDGFRα) mutations are considered wild-type (WT), and their diverse molecular alterations and biological behaviors remain uncertain. They are usually not sensitive to tyrosine kinase inhibitors (TKIs). Recently, some molecular alterations, including neurotrophic tyrosine receptor kinase (NTRK) fusions, have been reported in very few cases of WT GISTs. This novel finding opens the window for the use of tropomyosin receptor kinase (TRK) inhibitor therapy in these subtypes of GIST. Herein, we report a new case of NTRK-fused WT high-risk GIST in a female patient with a large pelvic mass (large dimension of 20 cm). The tumor was removed, and the histopathology displayed spindle-predominant morphology with focal epithelioid areas, myxoid stromal tissue, and notable lymphoid infiltration with tertiary lymphoid structures. Ten mitoses were quantified in 50 high-power fields without nuclear pleomorphism. DOG1 showed strong and diffuse positivity, and CD117 showed moderate positivity. Succinate dehydrogenase subunit B (SDHB) was retained, Pan-TRK was focal positive (nuclear pattern), and the proliferation index Ki-67 was 7%. Next-generation sequencing (NGS) detected an ETV6::NTRK3 fusion, and this finding was confirmed by fluorescence in situ hybridization (FISH), which showed NTRK3 rearrangement. In addition, an RB1 mutation was found by NGS. The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered. After 3 months of follow-up, a new CT scan showed a complete response. Based on our results and the cases from the literature, GISTs with NTRK fusions are very uncommon so far; hence, further screening studies, including more WT GIST cases, may increase the possibility of finding additional cases. The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with NTRK fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option.

A shared origin from a common ancestor: A case report of two histologically different tumors.

The origin of tumors has been under discussion over the years. Different theories have been suggested to explain this phenomenon. Among them, the Cancer-Stem Cells model, is one of the most outstanding. In this study, we reported a case of a 72-year-old man who presented two histologically different tumors with a 7-years gap, a Penile Squamous Cell Carcinoma and a Pleomorphic Undifferentiated Sarcoma, that share some molecular features. Phonotypical differences were showed and confirmed at histological and IHC levels. Molecular analysis showed an HPV infection in the carcinoma. Additionally, sequencing results revealed common (CDKN2A and TERT) and exclusive (FBXW7 and TP53) genetic alterations in both tumors (Table 1). The possible germline origin of common mutations was discarded after negative germline testing. Here we describe, for the first time a clinical case of a possible origin of two histologically different tumors from a common ancestor based on molecular data. Even if different hypothesis appear as possible, the Cancer Stem Cell-based model appears as the most suitable.

Intimal Sarcoma with MDM2/CDK4 Amplification and p16 Overexpression: A Review of Histological Features in Primary Tumor and Xenograft, with Immunophenotype and Molecular Profiling.

Intimal sarcomas (IS) are rare malignant mesenchymal tumors arising in large blood vessels of the systemic and pulmonary circulation and also in the heart. They are morphologically similar to other spindle cell, poorly differentiated sarcomas. The prognosis is poor and depends mainly on surgical options. Three cases of IS were collected from two institutions. Clinical data were retrieved and histological study was performed. A wide immunohistochemical panel was analyzed. FISH of MDM2 gene was performed, and a molecular study with NGS was implemented in all cases. The mean age of our cases was 54 years. Histologically, the tumors presented a diffuse growth pattern with heterogeneous atypical epithelioid or spindle cells and extensive thrombosed areas. All cases presented intense immunoexpression for MDM2, CDK4, CD117, c-myc, PDGFRA, and p16. PDGFRA, HTERT, and pan-TRK gained expression, while p16 lost intensity, being weaker in both the local recurrences and xenografts. The three cases showed amplification of MDM2 by FISH. NGS analysis revealed amplifications in the CDK4, PDGFRA, and KIT genes, together with BRAF mutation and KRAS amplification. P16 was expressed in all cases, losing intensity in local recurrence and xenografts. Two new alterations, a BRAF mutation and a KRAS amplification, were detected by NGS in different tumors, opening up new therapeutic options for these patients.

Liquid biopsy: possibilities and limitations in uro-oncology. / Biopsia líquida: posibilidades y limitaciones en uro-oncología.

In the recent years, research in oncologyhas focused on liquid biopsies, which rely on thedetection of cancer-derived components, includingcirculating tumor cells (CTCs), circulating tumor DNA(ctDNA), circulating free RNA (cfRNA), and extracellularvesicles (EVs), in the biofluids of patients, providinggenomic, epigenetic and transcriptomic, informationabout tumors and metastatic sites. In this reviewwe collect current evidence regarding the potentialof liquid biopsies for the diagnosis and follow-up ofuro-oncology patients, as well as the advantages andlimitations of these approaches. Although promising,the way in which this methodology must be incorporatedinto the clinical routine needs to be still definedboth at the pre-analytical and analytical level beforetheir clinical utility is demonstrated.

En los últimos años, la investigación enoncología se ha centrado en las biopsias líquidas, quese basan en la detección de elementos derivados delcáncer, incluyendo las células tumorales circulantes(CTCs), el ADN tumoral circulante (ctDNA), el ARN librecirculante (cfRNA), y las vesículas extracelulares(EVs) en los biofluidos de los pacientes, proporcionandoinformación genómica, epigenética y transcriptómicade los tumores y sus metástasis. En estarevisión recogemos la evidencia actual a cerca delpotencial de las biopsias líquidas para el diagnósticoy el seguimiento de los pacientes uro-oncológicos,sus ventajas y sus limitaciones. Aunque su potenciales prometedor, la forma en que esta metodología hade incorporarse a la clínica asistencial necesita definirsetanto a nivel pre-analítico como analítico antesde que se pueda demostrar su utilidad clínica.