Role of the Immunohistochemical ZEB1 Expression in Uterine Mesenchymal Neoplasms

The distinction of mesenchymal tumors of the uterus is a frequent diagnostic challenge in gynecologic pathology. Especially, distinguishing low-grade endometrial stromal sarcoma (ESS) from leiomyoma or distinguishing low-grade ESS from high-grade ESS can be difficult. Epithelial-mesenchymal transition (EMT) is a physiological and pathological process in which epithelial cells lose their morphological features, become elongated and acquire mesenchymal traits. The signaling pathway of Zinc finger E-box binding homeobox 1 (ZEB1) is one of the most significant pathways involved in the EMT process and it has a crucial role in cancer progression, metastasis, and therapy resistance. We studied a series of 69 uterine mesenchymal neoplasms including 18 endometrial stromal sarcomas (10 cases of low grade and 8 cases of high grade endometrial stromal sarcomas), 26 leiomyosarcomas (8 cases of grade 1 and 19 cases of grade 2-3 leiomyosarcomas), 15 leiomyomas, and 10 rhabdomyosarcomas, using an antibody ZEB1. We graded the leiomyosarcomas depending on the FNCLCC grading system. It was observed that leiomyosarcoma was more intensely stained with ZEB1 than leiomyoma (P < 0.001) and high-grade ESS was significantly more intensely stained with ZEB1 protein than low-grade ESS (P < 0.004). It also was observed that high-grade leiomyosarcoma was significantly more intensely stained with ZEB1 protein than low-grade leiomyosarcoma (P < 0.000). Our data suggest that Zeb1 can be used to differentiate high-grade sarcomas from their low-grade counterparts as well as benign and malignant smooth muscle tumors of the uterus.

Schwannoma of the Appendix Orifice

Schwannomas are rare mesenchymal tumors. They are usually diagnosed incidentally during endoscopic or diagnostic imaging for another reason. Malignant transformation is rare. In this case report, we present an incidental schwannoma protruding through the appendiceal orifice diagnosed during endoscopy. A healthy 56-year-old female underwent a surveillance colonoscopy for family history of colorectal cancer. A prominent and edematous appendiceal orifice was noted, and the area was aggressively biopsied. Histopathological assessment revealed a benign schwannoma. Computerized topography was unremarkable. Subsequently, the patient underwent a right hemicolectomy. Patient is scheduled to undergo routine surveillance in three years. Grossly, schwannomas are white, encapsulated, and well-circumscribed lesions that stain strongly positive for S100, GFAP, and CD57. Histologically, schwannomas demonstrate spindle cell proliferation. Several imaging modalities have been utilized in the diagnosis and management of mesenchymal neoplasms. Despite the benign nature of the diagnosis, complete surgical resection with clear margins remains the gold standard management strategy. Our case highlights the presence of a relatively uncommon tumor in an unusual anatomical location.

Immunohistochemical features of gastrointestinal stromal tumors and their role for differential diagnosis and prognosis

The aim. To clarify all most important immunohistochemical features of gastrointestinal stromal tumors with different histological patterns and analyze the role of expression of Ki-67, MMP-9, VEGF and p16ink4A as a predictive markers of tumor progression. Materials and methods. The study is based on analysis of 100 primary GISTs for description of their morphological features and 36 GISTs taken from this 100 for study of prognostic markers. Results. All spindle cell GISTs have shown diffuse expression of CD117 in tumor cells. The levels of CD117 expression varied from strong expression (3+) until mild expression (1+). Strong expression were seen in 75,8 % of spindle cell GISTs. Epithelioid GISTs demonstrated heterognous moderate or mild expression of CD117. All primary epithelioid GISTs from patients that had relapse of tumor in period from 1 till 3 years demonstrated focal mild expression of CD 117 in tumor cells. Expression of DOG-1 were seen in all 100 cases of GISTs, that were included in our study. The strong expression of DOG-1 (3+) were seen in all 45 GISTs that had low mitotic rate (≤5 mitoses per 50HPF) and not associated with their histological pattern. GISTs with high mitotic rate demonstrated heterogeneous expression of DOG-1 in tumors: moderate expression (2+) with patchy areas of strong expression (3+). Expression of CD56 was not found in spindle cell GISTs, but single tumor cells of epithelioid GISTs that had high mitotic rate demonstrated expression of this marker. The average expression of p16ink4A were higher in tumors that gave relapses compared with tumors without relapses (50,3 % versus 5,7 % respectively, U-test=16.5; p≤0,01).The average expression of MMP-9 also were significantly higher in GISTs that gave relapses: 63,2 % compared with 13,4 % in GISTs without relapse (U-test=16; p≤0 ,01).The strong VEGF expression was found in 66,7 % of GISTs that had relapses and only in 8,3 % of GISTs without relapses. 50 % of GISTs without relapses was negative for VEGF. Finally, the average expression of Ki-67 were 13,4 % in GISTs with relapses and 8,7 % in GISTs without them (U-test=16; p≤0,01). Conclusion. We highly recommend using DOG-1 for epithelioid GISTs. Additionally in epithelioid GISTs can be used CD56 that can give focal positive reaction in some tumour cells. The following minimal panel of markers for differential diagnosis of spindled GISTs from other mesenchymal tumors of gastrointestinal tract is proposed: CD117, DOG-1 and SMA, where the first too markers will demonstrated the moderate or strong diffuse expression and SMA can be occasionally positive in some tumor cells. p16ink4A, ki-67, VEGF and MMP-9 can be used as additional prognostic markers in GISTs.

CLINICOPATHOLOGIC AND MOLECULAR ANALYSIS OF A SINGLE BCOR-CCNB3+ UNDIFFERENTIATED SARCOMA OF THE KIDNEY CONFERS SIGNIFICANT EPIGENETIC ALTERATIONS

Undifferentiated soft tissue sarcomas (UDSTS ) are a group of mesenchymal tumors that remain a diagnostic challenge due to their morphologic heterogeneity and unclear histologic origin (Peters et al. 2015b). In this case report, we present the first multi-omics molecular signature for a BCOR-CCNB3 sarcoma (BCS) that includes mutation analysis, gene expression, DNA methylation, and mi-RNA expression. We identify a paucity of additional mutations in this tumor and detail that there is significant dysregulation of gene expression of epigeneic remodeling agents including key members of the PRC, Sin3A/3b, NuRD, and NcoR/SMRT complexes and the DNA methyltransferases DNMT1, DNMT3a, and DNMT3b. This is accompanied by significant DNA methylation changes and dysregulation of multiple miRNA with known links to tumorigenesis. This study significantly increases our understanding of the BCOR effects on fusion positive undifferentiated sarcomas at both the genomic and epigenomic level and suggests that as better-tailored and more refined treatment algorithms continue to evolve, epigenetic modifying agents should be further evaluated for their efficacy against these tumors.

Transvaginal Excision of Rectal Gastrointestinal Stromal Tumor: A Safe Minimally Invasive Approach

<b><i>Introduction:</i></b> Gastrointestinal stromal tumors (GISTs), the specific kit-positive mesenchymal tumors, are rarely found in the anorectum and account for 5% of all GIST cases. Surgical excision remains the main treatment for anorectal GIST. The available techniques include enucleation transanal excision or sometimes an abdominoperineal resection for large or low tumors. <b><i>Case Study:</i></b> We present a middle-aged female with a complaint of intermittent rectal pain for 1 year. Diagnostic workup detected a mass in the rectovaginal septum. A transvaginal excision was performed. Final histopathology showed rectal GIST. On regular follow-up visits, there was no detectable recurrence, and her anal pain disappeared completely. <b><i>Discussion:</i></b> Colorectal GIST accounts for only 0.1% of all colorectal tumors; this infrequency has led to a controversy in its diagnosis and management. Nevertheless, surgery remains a cornerstone element in the management of rectal GISTs. Different resection methods have been described in the literature, ranging from less-invasive approach such as transanal excision to a more radical one like an abdominoperineal resection. As there is no standard approach, choosing which one to perform depends on the tumor size, its location, and the surgeon’s preference. <b><i>Conclusion:</i></b> Transvaginal excision could be considered a safe minimally invasive approach for low-lying rectal GISTs.

New Aspects of Sarcomas of Uterine Corpus—A Brief Narrative Review

Sarcomas of the uterine corpus are rare malignant neoplasms, which are further classified into mesenchymal tumors, and mixed (epithelial plus mesenchymal) tumors. The main issues concerning these neoplasms are the small number of clinical trials, insufficient data from evidence-based medicine, insignificant interest from the pharmaceutical industry, all of which close a vicious circle. The low frequency of these malignancies implies insufficient experience in the diagnosis, hence incomplete surgical and complex treatment. Additionally, the rarity of these sarcomas makes it very difficult to develop clinical practice guidelines. Preoperative diagnosis, neoadjuvant and adjuvant chemoradiation, target and hormone therapies still raise many controversies. Disagreements about the role and type of surgical treatment are also often observed in medical literature. There are still insufficient data about the role of pelvic lymph node dissection and fertility-sparing surgery. Pathologists’ experience is of paramount importance for an accurate diagnosis. Additionally, genetics examinations become part of diagnosis in some sarcomas of the uterine corpus. Some gene mutations observed in uterine sarcomas are associated with different outcomes. Therefore, a development of molecular classification of uterine sarcomas should be considered in the future. In this review, we focus on the epidemiology, pathogenesis, pathology, diagnosis and treatment of the following sarcomas of the uterine corpus: leiomyosarcoma, low- and high-grade endometrial stromal sarcomas, undifferentiated sarcoma and adenosarcoma. Uterine carcinosarcomas are excluded as they represent an epithelial tumor rather than a true sarcoma.

Deep Convolutional Neural Networks Detect Tumor Genotype from Pathological Tissue Images in Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GIST) are common mesenchymal tumors, and their effective treatment depends upon the mutational subtype of the KIT/PDGFRA genes. We established deep convolutional neural network (DCNN) models to rapidly predict drug-sensitive mutation subtypes from images of pathological tissue. A total of 5153 pathological images of 365 different GISTs from three different laboratories were collected and divided into training and validation sets. A transfer learning mechanism based on DCNN was used with four different network architectures, to identify cases with drug-sensitive mutations. The accuracy ranged from 87% to 75%. Cross-institutional inconsistency, however, was observed. Using gray-scale images resulted in a 7% drop in accuracy (accuracy 80%, sensitivity 87%, specificity 73%). Using images containing only nuclei (accuracy 81%, sensitivity 87%, specificity 73%) or cytoplasm (accuracy 79%, sensitivity 88%, specificity 67%) produced 6% and 8% drops in accuracy rate, respectively, suggesting buffering effects across subcellular components in DCNN interpretation. The proposed DCNN model successfully inferred cases with drug-sensitive mutations with high accuracy. The contribution of image color and subcellular components was also revealed. These results will help to generate a cheaper and quicker screening method for tumor gene testing.

Review of Management of Gastrointestinal Stromal Tumor in Low-Resource Centers

Gastrointestinal stromal tumors (GIST) account for 1% to 3% of gastrointestinal tract tumors and are the most common of the mesenchymal tumors. Carcinogenesis of GIST arises in the interstitial cells of Cajal (ICC) and in the myenteric plexus of the gastrointestinal tract due to a mutation of the kinase receptor (KIT, also known as CD117) and the platelet-derived growth factor A (PDGFA) gene leading to activation of the tyrosine kinase receptor. The exact incidence and prevalence of GIST is not known. Symptoms of GIST are non-specific; they present with GI bleeding due to ulceration (50%), abdominal pain (20% to 50%), dysphagia (esophageal GIST) and GI obstruction (10% to 30%) (7,10). Signs include abdominal mass and fullness. A computerized tomographic (CT) scan is the preferred imaging to evaluate GIST. Diagnosis is confirmed by immunohistochemical (IHC) staining a of biopsy sample for medical treatment tyrosine kinase inhibitors (TKI). Surgical resection with negative microscopic margins is the gold standard treatment of GIST. TKI are required for tumor reduction to increase chances of respectability (neoadjuvant therapy) or to prevent recurrence and reduce the progression of advanced, resectable GIST.