EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review

EWSR1 belongs to the FET family of RNA-binding proteins including also Fused in Sarcoma (FUS), and TATA-box binding protein Associated Factor 15 (TAF15). As consequence of the multifunctional role of EWSR1 leading to a high frequency of transcription of the chromosomal region where the gene is located, EWSR1 is exposed to aberrations such as rearrangements. Consecutive binding to other genes leads to chimeric proteins inducing oncogenesis. The other TET family members are homologous. With the advent of widely used modern molecular techniques during the last decades, it has become obvious that EWSR1 is involved in the development of diverse benign and malignant tumors with mesenchymal, neuroectodermal, and epithelial/myoepithelial features. As oncogenic transformation mediated by EWSR1-fusion proteins leads to such diverse tumor types, there must be a selection on the multipotent stem cell level. In this review, we will focus on the wide variety of soft tissue and bone entities, including benign and malignant lesions, harboring EWSR1 rearrangement. Fusion gene analysis is the diagnostic gold standard in most of these tumors. We present clinicopathologic, immunohistochemical, and molecular features and discuss differential diagnoses.</jats:p

Laparoscopic resection of locally advanced gastrointestinal stromal tumour (GIST) of the stomach following neoadjuvant imatinib chemoreduction

AbstractIntroductionLaparoscopic resection of locally advanced gastrointestinal stromal tumours (GISTs) is rarely offered to patients as a first line of treatment.Presentation of casesWe present two cases of locally advanced gastric GISTs successfully treated with neoadjuvant imatinib and followed up by complete laparoscopic excision of the residual tumour mass. There was no evidence of local recurrence or distant metastases after a mean follow up of more than 40 months.DiscussionOver the last decade, the development of imatinib has totally revolutionized management of metastatic GISTs and it is now possible to achieve primary tumour downstaging of more than 80%. Unfortunately, current literature on laparoscopic excision of locally advanced gastric GISTs following neoadjuvant treatment of imatinib remains scarce. The present cases strongly suggest that this new therapeutic approach might become the preferred medical option in such clinical situation.ConclusionPatients with locally advanced non-metastatic gastric GISTs should be offered first-line neoadjuvant. Imatinib-based cytoreductive chemotherapy as an alternative to radical debulking surgery, as a substantial proportion of them will experience significant tumour shrinkage and therefore benefit from a much less invasive laparoscopic approach

Rare primary malignant bone sarcomas

open3noWe would like to thank Sarcoma European & LatinAmerican Network (SELNET), a consortium granted by European Commission (number: SEP-210512885), for supporting the idea of this special issRare primary malignant bone sarcomas (RPMBS), other than osteosarcoma, chondrosarcoma, chordoma, and Ewing sarcoma, account for about 5-10% of primary bone tumors and represent a major diagnostic challenge. These tumors include spindle cell and round cell sarcoma entities, hemangiopericytoma-like and vascular tumors. Additionally, several histotypes, traditionally described in the soft tissues, such as myxofibrosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumor of bone, have been reported in patients with primary bone tumors. While wide surgical resection is the mainstay of local treatment, systemic therapy of these rare entities is controversial. Patients with undifferentiated spindle cell or pleomorphic high-grade tumors of bone, are usually treated with osteosarcoma-like chemotherapy, while patients with round cell and undifferentiated round cell tumors (URCTs), may respond to sarcoma treatment regimens for Ewing sarcoma patients. Studies on analogies and differences among these ultra-rare tumors have seldom been reported. This review describes relevance, clinical aspects, diagnostic procedures, staging, treatment recommendations, and current research in this composite tumor group.openPalmerini E.; Righi A.; Staals E.L.Palmerini E.; Righi A.; Staals E.L

Rationale for early detection of EWSR1 translocation-associated sarcoma biomarkers in liquid biopsy

Sarcomas are mesenchymal tumours that often arise and develop as a result of chromosomal translocations, and for several forms of sarcoma the EWSR1 gene is a frequent translocation partner. Sarcomas are a rare form of malignancy, which arguably have a proportionally greater societal burden that their prevalence would suggest, as they are more common in young people, with survivors prone to lifelong disability. For most forms of sarcoma, histological diagnosis is confirmed by molecular techniques such as FISH or RT-PCR. Surveillance after surgical excision, or ablation by radiation or chemotherapy, has remained relatively unchanged for decades, but recent developments in molecular biology have accelerated the progress towards routine analysis of liquid biopsies of peripheral blood. The potential to detect evidence of residual disease or metastasis in the blood has been demonstrated by several groups but remains unrealized as a routine diagnostic for relapse during remission, for disease monitoring during treatment, and for the detection of occult, residual disease at the end of therapy. An update is provided on research relevant to the improvement of the early detection of relapse in sarcomas with EWSR1-associated translocations, in the contexts of biology, diagnosis, and liquid biopsy

Neoplasmas gastrointestinais primários não linfoides em cães no Rio Grande do Sul

Gastrointestinal neoplasms (GIN) are uncommon in dogs, but they mainly show malignant behavior and poor prognosis. The types of GIN in dogs and their frequency, as well as their epidemiological and histopathological characteristics were analyzed through a retrospective study of biopsies from 24.711 dogs from 2005 to 2017. Additionally, histological sections of neoplasms were subjected to immunohistochemistry (IHC) using antibodies against pancytokeratin, vimentin, smooth muscle actin, c-Kit, S-100, CD31, CD79αcy, and neuron specific enolase. Of the total samples from dogs analyzed, 88 corresponded to GIN. Neoplasms occurred more frequently in purebred dogs (64.8%, 57/88), males (53.4%, 47/88), with a median age of 10 years. The intestine was affected by 84.1% (74/88) of the cases. Of these, the large intestine was the most affected (67.6%, 50/74). Most of the neoplasms had malignant behavior (88.6%, 78/88). Regarding the classification of neoplasms, 46.6% (41/88) of the diagnoses corresponded to epithelial, 46.6% (41/88) were mesenchymal, 5.7% (5/88) were hematopoietic, and 1.1% (1/88) was neuroendocrine. The most frequently diagnosed neoplasms were papillary adenocarcinoma (19.3%, 17/88), leiomyosarcoma (17.0%, 15/88), gastrointestinal stromal tumors (GISTs) (12.5%, 11/88), and leiomyoma (5.0%, 8/88). Adenocarcinomas were located mainly in the rectum, whereas leiomyosarcomas and GISTs developed mainly in the cecum. Epithelial neoplasms showed a greater potential for lymphatic invasion whereas mesenchymal neoplasms appeared to be more expansive with intratumoral necrosis and hemorrhage. Immunohistochemistry was found to be an important diagnostic technique for the identification of infiltrating cells in carcinomas and an indispensable technique for the definitive diagnosis of sarcomas.Neoplasmas gastrointestinais (NGI) são pouco comuns em cães, mas possuem principalmente comportamento maligno e prognóstico reservado. Os tipos de NGI em cães e sua frequência, bem como características epidemiológicas e histopatológicas foram analisados por meio de um estudo retrospectivo dos exames de biópsias de 24.711 cães entre os anos de 2005 a 2017. Adicionalmente, cortes histológicos de NGI foram submetidos à técnica de imuno-histoquímica (IHQ), utilizando os anticorpos anti-pancitoqueratina, vimentina, actina de músculo liso, c-Kit, S-100, CD31, CD79αcy e enolase neurônio específica. Do total de cães analisados, 88 corresponderam a NGI não linfoides. Os neoplasmas ocorreram com maior frequência em cães de raça pura (64,8%, 57/88), machos (53,4%, 47/88), com mediana de idade de 10 anos. O intestino foi acometido em 84,1% dos casos (74/88). Destes, o intestino grosso foi o segmento mais afetado (67,6%, 50/74). A maior parte dos neoplasmas tinha comportamento maligno (88,6%, 78/88). Quanto à classificação, 46,6% (41/88) dos diagnósticos corresponderam a neoplasmas epiteliais, 46,6% (41/88) mesenquimais, 5,7% (5/88) hematopoiéticos e 1,1% (1/88), neuroendócrino. Os neoplasmas mais frequentemente diagnosticados foram adenocarcinoma papilar (19,3%, 17/88), leiomiossarcoma (17,0%, 15/88), tumor estromal gastrointestinal (GIST) (12,5%, 11/88) e leiomioma (12,5%, 8/88). Adenocarcinomas localizavam-se principalmente no reto, enquanto leiomiossarcoma e GISTs desenvolveram-se principalmente no ceco. Os neoplasmas epiteliais demonstraram um potencial maior de invasão linfática enquanto que os mesenquimais aparentaram ser mais expansivos, com necrose e hemorragia intratumorais. A imuno-histoquímica mostrou ser uma técnica diagnóstica importante para a identificação de células neoplásicas infiltravas no caso dos carcinomas e uma técnica indispensável para o diagnóstico definitivo de sarcomas

Identification of c-KIT mutation on exons 9 and 11 in gastrointestinal stromal tumour

Gastrointestinalni stromalni tumori (GIST) su najčešći primarni mezenhimalni tumori gastrointestinalnog trakta, a karakterizira ih prekomjerna ekspresija i mutacije c-KIT receptora tirozin kinaze. Somatske mutacije koje su rezultat konstitutivne aktivacije KIT kinaze su utvrđene u brojnim kliničkim studijima GIST-a, iako se mutacije pojavljuju različitom učestalošću. U nekoliko izvještaja je potvrđeno da su mutacije gena KIT najizraženije kod malignih GIST-a nego u benignim lezijama, posebice u eksonima 9 i 11, za koje je dokazano da imaju negativni prognostički faktor. U ovom su radu analizirane mutacije direktnim sekvenciranjem umnoženih dijelova DNA eksona 9 i 11 u 12 uzoraka GIST-a. Analizom uzoraka tkiva uklopljenog u parafin od 12 bolesnika s operiranim GIST-om pronađeno ih je devet (75%) s missense mutacijama odnosno nukleotidnim supstitucijama u eksonu 11, jedan s mutacijom delecije baza, isto u eksonu 11, a u eksonu 9 je u jednom uzorku uz missense mutaciju pronađena i insercijska mutacija.Gastrointestinal stromal tumors (GISTs) are the most common primary mesenchymal tumours of the gastrointestinal tract and are characterized by overexpression and mutation of c-KIT, receptor tyrosine kinase. Somatic mutations that result in constitutive activation of KIT kinase have been identified in a number of clinical studies of GISTs, although the reported frequency of these mutations has varied over a wide range. Several reports have suggested that KIT gene mutations are more common in malignant GISTs than in benign lesions, and it has been proposed that mutations in exon 9 and exon 11 of KIT are negative prognostic factor. In this study mutations were characterised by direct DNA sequencing for screening polymerase chain reaction amplimers of exons 9 and 11 from GIST genomic DNA. Missense mutations within the exon 11 have been identified in nine (75%) of twelve patients, one patient had a deletion in exon 11 and one patient had a insertion within exon 9 of KIT

Granular cell tumor of the breast: a multidisciplinary challenge

Granular cell tumors are rare soft tissue tumors; they are almost never malignant, but can mimic a carcinoma clinically, radiologically and microscopically. The finding of a suspicious lump often entails subsequent diagnostic procedures that can pose significant anxiety on patients before reaching a challenging differential diagnosis. The physical and psychological burden is even more significant when such findings occur during the follow up of a previous oncologic condition. Sometimes the fear for a potential local or distant recurrence can be responsible for a misdiagnosis and lead to patient overtreatment

The wide morphological spectrum of deep (Aggressive) angiomyxoma of the vulvo-vaginal region: A clinicopathologic study of 36 cases, including recurrent tumors

Background: Deep angiomyxoma (DAM) is currently included in the category of "specific stromal tumors of the lower female genital tract", along with angiomyofibroblastoma, cellular angiofibroma and myofibroblastoma. Given the high rate of local recurrences, it is crucial to recognize DAM from other tumors that possess indolent behaviour. In the present paper, we analyzed the morphological and immunohistochemical features of 42 surgically-resected vulvo-vaginal DAMs (36 primary and 6 recurrent lesions) in order to widen the morphological spectrum of this uncommon tumor. Methods: A series of 36 cases of surgically-resected primary vulvo-vaginal DAMs were retrospectively collected. Locally recurrent tumors were also available for six of these cases. Results: Out of the primary tumors, 25 out of 36 exhibited the classic-type morphology of DAM. In the remaining cases (11/36 cases), the following uncommon features, which sometimes coexist with one another, were observed: (i) alternating myxoid and collagenized/fibrous areas; (ii) hypercellular areas; (iii) neurofibroma-like appearance; (iv) perivascular hyalinization; (v) microcystic/reticular stromal changes; (vi) "microvascular growth pattern"; (vii) perivascular cuffing; (viii) nodular leiomyomatous differentiation; (ix) hypocellular and fibro-sclerotic stroma. Among the six locally recurrent tumors the following features were observed: (i) classic-type morphology; (ii) hypocellular fibro-sclerotic stroma; (iii) extensive perivascular hyalinization, lumen obliteration and formation of confluent nodular sclerotic masses; (iv) hypercellularity. Immunohistochemically, the neoplastic cells of classic-type DAM in both primary and recurrent tumors were diffusely stained with desmin, suggesting a myofibroblastic nature; in contrast, the neoplastic cells showing elongated fibroblastic-like morphology and set in collagenized/fibrosclerotic stroma in both primary and recurrent tumors were negative or only focally stained with desmin, which is consistent with a fibroblastic profile. Conclusion: Although diagnosis of DAM is usually straightforward if typical morphology is encountered, diagnostic problems may arise when a pathologist is dealing with unusual morphological features, especially hypercellularity, extensive collagenous/fibrosclerotic stroma or neurofibroma-like appearance