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.

Neutrophil Extracellular Traps and Cancer: Trapping Our Attention with Their Involvement in Ovarian Cancer.

Neutrophils, the most abundant circulating leukocytes, play a well-known role in defense against pathogens through phagocytosis and degranulation. However, a new mechanism involving the release of neutrophil extracellular traps (NETs) composed of DNA, histones, calprotectin, myeloperoxidase, and elastase, among others, has been described. The so-called NETosis process can occur through three different mechanisms: suicidal, vital, and mitochondrial NETosis. Apart from their role in immune defense, neutrophils and NETs have been involved in physiopathological conditions, highlighting immunothrombosis and cancer. Notably, neutrophils can either promote or inhibit tumor growth in the tumor microenvironment depending on cytokine signaling and epigenetic modifications. Several neutrophils' pro-tumor strategies involving NETs have been documented, including pre-metastatic niche formation, increased survival, inhibition of the immune response, and resistance to oncologic therapies. In this review, we focus on ovarian cancer (OC), which remains the second most incidental but the most lethal gynecologic malignancy, partly due to the presence of metastasis, often omental, at diagnosis and the resistance to treatment. We deepen the state-of-the-art on the participation of NETs in OC metastasis establishment and progression and their involvement in resistance to chemo-, immuno-, and radiotherapies. Finally, we review the current literature on NETs in OC as diagnostic and/or prognostic markers, and their contribution to disease progression at early and advanced stages. The panoramic view provided in this article might pave the way for enhanced diagnostic and therapeutic strategies to improve the prognosis of cancer patients and, specifically, OC patients.

Increased levels of NETosis biomarkers in high-grade serous ovarian cancer patients' biofluids: Potential role in disease diagnosis and management.

Introduction: High-grade serous ovarian cancer (HGSOC) is the second most frequent gynecological malignancy but the most lethal, partially due to the spread of the disease through the peritoneal cavity. Recent evidence has shown that, apart from their role in immune defense through phagocytosis and degranulation, neutrophils are able to participate in cancer progression through the release of neutrophil extracellular traps (NETs) in a process called NETosis. NETs are composed of DNA, histones, calprotectin, myeloperoxidase (MPO) and elastase and the NETosis process has been proposed as a pre-requisite for the establishment of omental metastases in early stages of HGSOC. Nevertheless, its role in advanced stages remains to be elucidated. Therefore, our principal aim is to characterize a NETosis biomarker profile in biofluids from patients with advanced HGSOC and control women. Methods: Specifically, five biomarkers of NETosis (cell-free DNA (cfDNA), nucleosomes, citrullinated histone 3 (citH3), calprotectin and MPO) were quantified in plasma and peritoneal fluid (PF) samples from patients (n=45) and control women (n=40). Results: Our results showed that HGSOC patients presented a higher concentration of cfDNA, citH3 and calprotectin in plasma and of all five NETosis biomarkers in PF than control women. Moreover, these biomarkers showed a strong ability to differentiate the two clinical groups. Interestingly, neoadjuvant treatment (NT) seemed to reduce NETosis biomarkers mainly systemically (plasma) compared to the tumor environment (PF). Discussion: In conclusion, NETosis biomarkers are present in the tumor environment of patients with advanced HGSOC, which might contribute to the progression of the disease. Besides, plasma cfDNA and calprotectin could represent minimally invasive surrogate biomarkers for HGSOC. Finally, NT modifies NETosis biomarkers levels mainly at the systemic level.

Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis.

Glioblastoma multiforme (GB) is one of the most aggressive tumors. Despite continuous efforts to improve its clinical management, there is still no strategy to avoid a rapid and fatal outcome. EGFR amplification is the most characteristic alteration of these tumors. Although effective therapy against it has not yet been found in GB, it may be central to classifying patients. We investigated somatic-copy number alterations (SCNA) by multiplex ligation-dependent probe amplification in a series of 137 GB, together with the detection of EGFRvIII and FISH analysis for EGFR amplification. Publicly available data from 604 patients were used as a validation cohort. We found statistical associations between EGFR amplification and/or EGFRvIII, and SCNA in CDKN2A, MSH6, MTAP and ADD3. Interestingly, we found that both EGFRvIII and losses on ADD3 were independent markers of bad prognosis (p = 0.028 and 0.014, respectively). Finally, we got an unsupervised hierarchical classification that differentiated three clusters of patients based on their genetic alterations. It offered a landscape of EGFR co-alterations that may improve the comprehension of the mechanisms underlying GB aggressiveness. Our findings can help in defining different genetic profiles, which is necessary to develop new and different approaches in the management of our patients.

Identification of a Novel BRCA1 Alteration in Recurrent Melanocytoma Resulting in Increased Proliferation.

Primary meningeal melanocytomas are rare tumors of the central nervous system. Although they are considered benign neoplasms, some reports describe recurrent rates up to 45%. Little is known about their genetic and epigenetic landscape because of their infrequency. Even less has been described about markers with prognostic value. Here we describe a patient who developed a primary meningeal melanocytoma, suffered 3 recurrences in a period of 6 years and died of the tumor. The genetic and epigenetic changes explored confirmed GNAQ mutation as an initiating event. We found an epigenetic alteration of GSTP1, a feature that has recently been described in meningiomas, from the beginning of the disease. In addition, there was loss of heterozygosity in BRCA1 beginning in the second recurrence that was linked to an increase in the proliferation index; this suggested a progression pathway similar to the one described in uveal melanomas. These findings underscore the necessity of further research focused on these tumors.

Granular cell tumor on the sole of a child: a case report.

Granular cell tumor, also known as Abrikossoff tumor, is a rare infrequent neoplasm of unclear etiology which has been rarely described in children. Involvement of the feet is extremely rare. We report a 7-year-old boy presenting a granular cell tumor on the sole.

Pseudoxantoma elasticum-like dermal elastolysis: a case report.

Elastic fibers are components of dermal connective tissue that can be affected in several acquired disorders. Recently, a new entity known as pseudoxanthoma-like papillary dermal elastolysis has been described. We present a case in a 61-year-old woman.

Poroid hidradenoma in a child: an unusual presentation.

Poroid neoplasm is a benign sweat gland neoplasm that accounts for 10% of sudoriferous tumors. Poroid hidradenoma is an uncommon variant that usually affects adults, with a peak of incidence in the seventh decade. It is rare in children. We report the first case of poroid hidradenoma presenting in a 13-year-old boy.

Lymphoepitelioma-like carcinoma of the skin: report of three cases.

Primary cutaneous lymphoepithelioma-like carcinoma (LELC) is an extremely rare cutaneous neoplasm with histopathological features similar to those seen in the undifferentiated subtype of nasopharyngeal carcinoma. Microscopically, the tumor is well circumscribed and is composed of irregular nests of malignant epithelial cells in a background of reactive lymphoid cells including mature plasma cells. Its histogenesis remains unknown although an adnexal or epidermic origin has been proposed, and despite its poorly differentiated histology, the LELC prognosis is relatively good. We describe three new cases of this entity that support an epidermic origin.

Eccrine angiomatous hamartoma in a child.

Eccrine angiomatous hamartoma (EAH) is a rare, benign malformation characterized by both eccrine and vascular components. It usually presents at birth or during early infancy and childhood as a nodule or a plaque, usually solitary, involving acral skin. Eccrine angiomatous hamartoma is usually asymptomatic, although focal hyperhidrosis, hypertrichosis, and pain can be observed. We report an additional case of this rare entity presenting in a 14-year-old boy.

Primary cutaneous mucoepidermoid carcinoma.

Mucoepidermoid carcinoma represents between 10-30% of primary carcinomas of the submandibulary, parotid and minor salivary glands. Cutaneous involvement is extremely rare and more, as a primary origin of the tumor. A few cases of primary mucoepidermoid carcinoma of the skin have been described. We report an 83-year-old man presenting a primary cutaneous mucoepidermoid carcinoma over his right cheek.

Immunohistochemical study as a tool in differential diagnosis of pediatric malignant rhabdoid tumor.

Malignant rhabdoid tumors (MRTs) are aggressive childhood neoplasms, occurring mainly in the kidney and brain. We describe 2 unusual cases of extrarenal and noncranial location (liver and soft tissue with dissemination) mimicking hepatoblastoma, neuroblastoma or Ewing sarcoma. Both cases revealed a polyphenotypic profile, combined with cytokeratin, vimentin, and CD99 expression. INI1/BAF-47 showed negative protein nuclear expression in both cases, suggesting a diagnosis of MRT. An extensive immunohistochemical panel was performed to exclude pediatric tumors reminiscent of MRT. The genetic studies failed to detected MYCN amplification, 11q23 deletion, and EWS break-apart positivity. No alterations of 22q integrity were demonstrated with the probes used for the study (N25 Di George/22q11.2, 22qter, and EWS/22q12). We discuss the differential diagnosis in pediatric polyphenotypic tumors (Wilms tumor, neuroblastoma, desmoplastic small round cell tumor, and Ewing sarcoma). Analysis of INI1/BAF-47 expression can offer important clues in the diagnosis of pediatric tumors with rhabdoid phenotype. The integration of clinical, morphologic, immunohistochemical, and genetic data is required to approach a correct diagnosis of pediatric tumor in unusual location with atypical or undifferentiated morphology.