Pathology Of Sarcomas Research Articles

1α,25(OH)2D3 regulates pro-angiogenic factors in endothelial cells transformed by Kaposi's sarcoma-associated herpesvirus G protein coupled receptor

When tumoral cell expansion exceeds the vascular supply, regions of hypoxia or low oxygen concentration are generated promoting the formation of new vessels through cell proliferation and migration. Viral G protein-coupled receptor (vGPCR) is associated to Kaposi's sarcoma pathology and induces a paracrine transformation when is stably expressed in murine endothelial cells activating hypoxia-induced transcription factors. Previously, we reported the antiproliferative actions of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in endothelial cells transformed by the vGPCR (SVEC-vGPCR). Herein, we further investigated if pro-angiogenic factors as AP-1, HIF-1α and VEGF are modulated by 1α,25(OH)2D3. We found by qRT-PCR analysis that the mRNA level of JunB, a negative regulator of cell proliferation, was similarly increased at all-time points tested after 1α,25(OH)2D3 treatment in SVEC-vGPCR cells. Also, mRNA levels of the pro-angiogenic factor c-Fos, which induces tumor invasion, were only decreased during one short period treatment. In addition, Hif-1α mRNA and protein levels were significantly reduced after 1α,25(OH)2D3 treatment in a VDR dependent fashion. However, mRNA levels of the angiogenic activator Vegf, promoted in turn by Hif-1α expression, were surprisingly high depending on VDR expression as well. Moreover, Egr-1, which has been reported to induce VEGF expression independently of HIF-1α, diminished its expression with 1α,25(OH)2D3 treatment, fact that was related to the decline of p-ERK1/2. Altogether, these results suggest a negative modulation of some pro-angiogenic factors like AP-1 and HIF-1α, as part of the antiproliferative mechanism of 1α,25(OH)2D3 in SVEC-vGPCR endothelial cells.

What's new in bone and soft tissue pathology 2023: guidelines for molecular testing.

Our understanding of bone and soft tissue tumors has thoroughly evolved as a consequence of modern molecular techniques. DNA and RNA sequencing methods play an important diagnostic and therapeutic role in sarcoma pathology. Herein, we discuss current guidelines and best practices for molecular testing in bone and soft tissue tumors.

Exploring real-world practices and challenges of sarcoma diagnosis in Morocco: A survey-based study among 144 pathologists.

Sarcoma diagnosis is a challenge for laboratories of cytopathology and anatomic pathology. We conducted this survey-based study to better elucidate real-world practices and challenges of sarcoma diagnosis. Methods: This was a cross-sectional study using an anonymous questionnaire. The survey was distributed among pathologists using snowball sampling. Descriptive statistics were used to report the finding of this survey. A total of 144 Moroccan pathologists were surveyed. Most respondents were from academic institutions (41.7%) and those with a specialization in sarcoma diagnosis represented 57%, through training using post-graduate fellowships followed by internships abroad and inter-university diplomas. Remarkably, 36.8% of participants reported no training on sarcoma pathology during their career. Regarding frequency of sarcoma diagnosis, 64.6% of pathologists reported having received less than one case of sarcoma per week and more than 70% did not receive sufficient information from referring clinicians. The majority of pathologists reported their nonattendance in multidisciplinary meetings. Morphology and immunohistochemistry were the most frequently used diagnostic tools, while fluorescence in situ hybridization and other molecular biology techniques were accessible for only 27% and 20.1% of pathologists, respectively. Response time during pathological diagnosis of sarcoma was 14 days according to 52.8% of surveyed participants. In addition, a second opinion was needed for 66% of pathologists. Specialized training on sarcoma pathology in Morocco is lacking. A national working group on sarcoma pathology is needed to provide second opinions, and therefore, improve the management of this malignancy of poor prognosis. (www.actabiomedica.it).

A rare case of clear cell sarcoma of the foot with a cascade of pathological misdiagnosis-the importance of expert sarcoma pathology.

Sarcoma pathology discrepancy is well known owing to the extremely heterogenous and rare nature of this tumour. Through this case, we want to highlight the difficulty that a patient has to undergo in a case of misdiagnosis. A 20-year-old male presented with swelling in the right foot for 4 months, which was initially diagnosed as alveolar rhabdomyosarcoma, subsequently as synovial sarcoma and finally as Ewing's sarcoma (based upon positive Ewing Sarcoma Breakpoint Region 1 (EWSR1) by fluorescence in situ hybridisation and he underwent neoadjuvant chemotherapy and surgical excision with grafting before he presented to our institute, where the pathologists reviewed the biopsy slides, which were positive for HMB45 and negative for Melan-A suggestive of clear cell sarcoma. The next-generation sequencing suggested EWSR1-ATF1 fusion, which again reinforced the diagnosis. This case throws light on the importance of expert pathology and interpreting molecular results in the right context.

Updates in Pathology for Retroperitoneal Soft Tissue Sarcoma.

Retroperitoneal tumors are extremely rare. More than 70% of primary retroperitoneal soft tissue tumors are malignant. The most common sarcomas in the retroperitoneum include liposarcomas and leiomyosarcoma, however other sarcomas, along with benign mesenchymal tumors, can occur. Sarcomas are a heterogenous group of tumors with overlapping microscopic features, posing a diagnostic challenge for the pathologist. Correct tumor classification has become important for prognostication and the evolving targeted therapies for sarcoma subtypes. In this review, the pathology of retroperitoneal soft tissue sarcomas is discussed, which is important to the surgical oncologist. In addition, less common sarcomas and benign mesenchymal tumors of the retroperitoneum, which may mimic sarcoma clinically and pathologically, are also discussed.

Machine learning for rhabdomyosarcoma histopathology

AbstractCorrectly diagnosing a rare childhood cancer such as sarcoma can be critical to assigning the correct treatment regimen. With a finite number of pathologists worldwide specializing in pediatric/young adult sarcoma histopathology, access to expert differential diagnosis early in case assessment is limited for many global regions. The lack of highly-trained sarcoma pathologists is especially pronounced in low to middle-income countries, where pathology expertise may be limited despite a similar rate of sarcoma incidence. To address this issue in part, we developed a deep learning convolutional neural network (CNN)-based differential diagnosis system to act as a pre-pathologist screening tool that quantifies diagnosis likelihood amongst trained soft-tissue sarcoma subtypes based on whole histopathology tissue slides. The CNN model is trained on a cohort of 424 centrally-reviewed histopathology tissue slides of alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma and clear-cell sarcoma tumors, all initially diagnosed at the originating institution and subsequently validated by central review. This CNN model was able to accurately classify the withheld testing cohort with resulting receiver operating characteristic (ROC) area under curve (AUC) values above 0.889 for all tested sarcoma subtypes. We subsequently used the CNN model to classify an externally-sourced cohort of human alveolar and embryonal rhabdomyosarcoma samples and a cohort of 318 histopathology tissue sections from genetically engineered mouse models of rhabdomyosarcoma. Finally, we investigated the overall robustness of the trained CNN model with respect to histopathological variations such as anaplasia, and classification outcomes on histopathology slides from untrained disease models. Overall positive results from our validation studies coupled with the limited worldwide availability of sarcoma pathology expertise suggests the potential of machine learning to assist local pathologists in quickly narrowing the differential diagnosis of sarcoma subtype in children, adolescents, and young adults.

New developments in the pathology and molecular biology of retroperitoneal sarcomas

Retroperitoneal sarcomas (RPS) refer to a heterogeneous group of malignancies of mesenchymal origin developing from retroperitoneal tissues and vessels. The most frequent RPS are well differentiated/dedifferentiated liposarcomas and leiomyosarcomas, but other rare histological subtypes can be observed. Over the last decade, significant advances have been made in the pathological and molecular characterization of sarcomas. These advances have led to major changes in their diagnostic management as well as in the development of new therapeutic strategies based on tumor biology and microenvironment. This review describes the current knowledge and recent findings in the pathology and molecular biology of the most frequent RPS subtypes.

Modeling fusion gene-associated sarcoma: Advantages for understanding sarcoma biology and pathology.

Disease-specific gene fusions are reportedly major driver mutations in approximately 30% of bone and soft tissue sarcomas. Most fusion genes encode transcription factors or co-factors that regulate downstream target genes, altering cell growth, lineage commitment, and differentiation. Given the limitations of investigating their functions in vitro, the generation of mouse models expressing fusion genes in the appropriate cellular lineages is pivotal. Therefore, we generated a series of mouse models by introducing fusion genes into embryonic mesenchymal progenitors. This review describes mouse models of Ewing, synovial, alveolar soft part, and CIC-rearranged sarcomas. Furthermore, we describe the similarities between these models and their human counterparts. These models provide remarkable advantages to identify cells-of-origin, specific collaborators of fusion genes, angiogenesis key factors, or diagnostic biomarkers. Finally, we discuss the relationship between fusion proteins and the epigenetic background as well as the possible role of the super-enhancers.

Who, how and what of pathology of soft tissue sarcoma

Who, how and what of pathology of soft tissue sarcoma

Ewing sarcoma of the kidney; a rare case report

Kidney cancer is considered as one of the commonest urological malignancies globally. Primitive neuroectodermal tumor and ewing sarcoma pathology are commonly found bone cancers within the daily clinical practice especially in adulthood.
 In this article we will discuss a rare case report of ewing sarcoma family variant (ESFV) within the renal pelvis. Chemotherapeutic and radiation protocols already used in bone ewing sarcoma have been exploited to treat this variant pathological malignancy in the kidney considering the metastatic presentation of the case. Hence, the response to some of these management lines was obvious during follow up appointments. Unfortunately, side effects were so severe especially the hematological adverse events. By conclusion, the administration of the same protocols as for bone ewnig sarcoma should be discussed carefully in treatment selection.

Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network.

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.

Head and neck sarcomas: the first report addressing the duration of symptoms and diagnostic work up

Background: Head and neck sarcomas are rare and difficult to diagnose and manage.Aim: To describe a population of patients with head and neck sarcomas focusing on the effect of symptom duration and time to diagnosis on mortality and recurrence risk.Materials and methods: Fifty-one patients treated in our department between 1998–2013 were retrospectively included. Patient and tumour characteristics as well as dates of interest were obtained from sarcoma registries, charts and pathology records. The effect of symptom duration and time to diagnosis on mortality and risk of recurrence was tested by multivariate analysis.Results: There was a wide range in symptom duration (1–144 months, median 5) and time for diagnosis (0–234 days, median 14) without significant effect on overall mortality, disease-specific mortality or risk of recurrence. Chondrosarcomas in the larynx dominated among the patients with the longest diagnostic duration.Conclusion and significance: The diagnostic process is challenging and in some cases of extremely long duration without effect on mortality. The symptom duration and time to diagnosis in relation to mortality and risk of recurrence has not previously been described. Early biopsy, better imaging and advanced pathological techniques can hopefully speed up the diagnostic process and reduce morbidity and mortality.

Copathology in Progressive Supranuclear Palsy: Does It Matter?

The influence of concomitant brain pathologies on the progression rate in PSP is unclear. To analyze the frequency and severity of copathologies and their impact on the progression in PSP. We analyzed clinic-pathological features of 101 PSP patients. Diagnoses and stages of copathologies were established according to standardized criteria, including Alzheimer's disease-related pathology, argyrophilic grains, Lewy-related pathology, transactive response DNA-binding protein 43 pathology, fused in sarcoma pathology, cerebral amyloid angiopathy, and small vessel disease. Demographic data and major clinical milestones (frequency and latency to onset) were extracted from patients' files. Only 8% of 101 patients presented with pure PSP pathology without any copathology. Alzheimer's disease-related pathology was the most frequent (84%), followed by argyrophilic grains (58%), both occurring as single copathology or in combination with other proteinopathies or cerebrovascular disease. Lewy-related and transactive response DNA-binding protein 43 copathology occurred rarely (8% and 6%, respectively). Fused in sarcoma-positive cases were not found. While being common, copathology was mostly mild in severity, with the exception of frequently widespread argyrophilic grains. Small vessel disease was also frequent (65%). Cerebral amyloid angiopathy occurred only in the presence of Alzheimer's disease-related changes (25%). The copathologies did not have major impact on prevalence and time frame of major disease milestones. In PSP, concomitant neurodegenerative proteinopathies or cerebrovascular diseases are frequent, but generally mild in severity. Our data confirmed that four repeat tau is still the most relevant target for PSP, whereas the impact of copathologies on progression rate appears to be of less importance. This is relevant information for the development of disease-modifying therapies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Sarcoma of the Uterus. Guideline of the DGGG and OEGGG (S2k Level, AWMF Register Number 015/074, February 2019).

Aims This is an official guideline published and coordinated by the German Society of Gynecology and Obstetrics (DGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). Because of their rarity and heterogeneous histopathology, uterine sarcomas are challenging in terms of how they should be managed clinically, and treatment requires a multidisciplinary approach. To our knowledge, there are currently no binding evidence-based recommendations for the appropriate management of this heterogeneous group of tumors. Methods This S2k guideline was first published in 2015. The update published here is the result of the consensus of a representative interdisciplinary group of experts who carried out a systematic search of the literature on uterine sarcomas in the context of the guidelines program of the DGGG, OEGGG and SGGG. Members of the participating professional societies achieved a formal consensus after a moderated structured consensus process. Recommendations The consensus-based recommendations and statements include the epidemiology, classification, staging, symptoms, general diagnostic work-up and general pathology of uterine sarcomas as well as the genetic predisposition to develop uterine sarcomas. Also included are statements on the management of leiomyosarcomas, (low and high-grade) endometrial stromal sarcomas and undifferentiated uterine sarcomas and adenosarcomas. Finally, the guideline considers the follow-up and morcellation of uterine sarcomas and the information provided to patients.

Fused in sarcoma (FUS) pathology observed in an autopsy case of ALS/MND-plus clinical syndrome

Fused in sarcoma (FUS) pathology observed in an autopsy case of ALS/MND-plus clinical syndrome

Discordance of Histo-pathological Diagnosis of Patients with Soft Tissue Sarcoma Referred to Tertiary Care Center

Background: Reaching the correct histo-pathological diagnosis of soft tissue sarcomas (STS) is a great challenge and is cornerstone for treatment planning. Need of expertise for diagnosis is limited due to the lack of dedicated expert sarcoma pathologists and oncologists in India. In this study we highlight the pattern of pathological diagnosis and its accuracy outside specialist centre. Methods: We performed retrospective analysis of all patients referred to us with a clinical or histopathologic diagnosis of STS over the period January 2016 to December 2017. According to the protocol, all patients had a review of histopathology diagnosis from our institute. The tissue blocks if available were reviewed and a fresh biopsy was performed when required. The histopathologic diagnosis was also reviewed in the joint clinic, giving clinico-radiological inputs to sarcoma pathologists. For the patients with outside diagnosis and discordant report, we divided them into major discrepancy (including change of diagnosis of sarcoma to benign or other histological entity that could potentially change the treatment plan) or minor discrepancy (like mild change in grade or histopathological diagnosis not affecting the treatment plan). Statistical analysis was done by SPSS ver 23.Results: There were 149 patients with median age of 36 years (range 14-77 years), and 93 patients (62.4%) were males. About 57% (85 cases) of patients had localized disease. Most common subtypes were synovial sarcoma (16%), liposarcoma (9%), soft tissue ewings sarcoma (9%), MPNST (9%), leiomyosarcoma (8%), and undifferentiated pleomorphic sarcoma (8%). Of 149 patients, 47 (31.5%) had not been worked up outside by immunohistochemistry or other molecular studies and thus comparison was not possible; while 4 patients couldn’t retrieve blocks and repeat biopsy could not be performed. Of 97 patients (biopsy = 84, FNAC = 13) who had diagnosis from outside, 37% had major discrepancy and 24% had minor discrepancy as compared with our diagnosis from the sarcoma specialists. Univariate analysis revealed that the major discrepancy was more in non-extremity than extremity STS (p = 0.003).Conclusion: Histopathologic diagnosis in more than half of patients referred from outside centers was discordant with respect to the diagnosis of our centre with major implications on 37% of cases. We believe this is due to the lack of sarcoma pathology experts, and they are virtually non-existent in the multidisciplinary clinic set up outside the tertiary care centres.

CORR® Tumor Board: Can Navigation Improve the Ability to Achieve Tumor-free Margins in Pelvic and Sacral Primary Bone Sarcoma Resections? A Historically Controlled Study

CORR® Tumor Board: Can Navigation Improve the Ability to Achieve Tumor-free Margins in Pelvic and Sacral Primary Bone Sarcoma Resections? A Historically Controlled Study

Unexpected uterine sarcomas in 4478 patients with electric power morcellation for leiomyomas

ObjectivesOur objective is to investigate the prevalence, pathology and prognosis of uterine sarcomas in laparoscopic hysterectomy/myomectomy with electric power morcellation for presumed leiomyomas. Study DesignWe retrospectively reviewed patients with laparoscopic power morcellation (LPM) for presumed leiomyomas in a Chinese tertiary institution by chart review from September 1, 2013 to December 31, 2016. ResultsTwenty-four in 4478 patients (0.54%) with LPM for presumed leiomyomas had unexpected cancers. The patients showed the highest frequency of occult cancers (10/375, 2.6%) at 51–60 years and lowest (0/255) before 30 years. The pathology included 14 endometrial stromal sarcomas (ESS) (low-grade 12 and high-grade 2), 9 leiomyosarcomas, and 1 malignant mixed mesodermal tumor. The patients underwent abdominal re-exploration including total hysterectomy with bilateral salpingo-oophorectomy and staging surgery. Three patients were at advanced FIGO stage (IIIb-IVb) and 21 at stage I. Seven patients recurred within 1–25 (mean 6.29) months including 5 leiomyosarcomas, 1 high-grade and 1 low-grade ESS. Four recurrent patients with leiomyosarcomas and one with high-grade ESS died of disease in 1–3 months. Seventeen patients had no relapse and were alive for 6–41 (mean 24) months. ConclusionsOur study suggests that patients with LPM for presumed leiomyomas appear to have a considerable risk of unexpected cancers. Moreover, morcellation is potentially associated with adverse prognosis in patients with high-grade sarcomas. Informed consent on unexpected cancers that should be discussed before morcellation.

The pathology of soft tissue sarcomas.

Soft tissue sarcomas represent a heterogeneous group of rare malignancies exhibiting mesenchymal differentiation with an overall incidence of around 5/100,000/year. Rarity and morphologic heterogeneity significantly affect diagnostic accuracy; therefore, expertise can be achieved only through access to large number of cases. Soft tissue sarcomas are currently classified on the basis of the 2013 WHO classification of soft tissue tumors that integrate conventional morphology with immunohistochemistry and molecular genetics. The morphologic diagnosis of sarcoma relies on the evaluation as well as the integration of four main features: the shape of the neoplastic cells; the pattern of growth; the quality of the background; the architecture of the vascular network. Immunohistochemical characterization plays a key role in the diagnostic workup of soft tissue sarcomas. The majority of classic differentiation markers tend to show good sensitivity, however, associated with rather limited specificity, making interpretation in context with morphology mandatory. Molecular genetics is increasingly used for diagnostic purposes to distinguish specific subtypes of sarcomas, to support diagnosis in non-canonical clinical presentations and also to distinguish true sarcomas from benign mimickers. With many exceptions, histologic typing does not provide sufficient information for predicting the clinical course of the disease and, therefore, grading systems based on histological parameters were introduced to provide a more accurate estimation of the degree of malignancy of tumors. The three-tiered system devised by the French Federation of Cancer Centers Sarcoma Group (FNCLCC) systems is widely adopted; however, several limitations exist that have led to the development of prognostic nomograms that incorporate the specific histotype as one of the relevant parameters.

Stem cell transcription factor SOX2 in synovial sarcoma and other soft tissue tumors

BackgroundSOX2 has gained considerable interest as a pluripotency inducing gene. Co-transfection of SOX2 together with NANOG, KLF4 and c-MYC into adult fibroblasts was able to generate pluripotent stem cells. SOX2 has been reported to be expressed in synovial sarcoma, a tumor being characterized by the SS18-SSX gene fusion forming part of the SWI/SNF chromatin remodeling complex that affects histone methylation. The role of SOX2 in this tumor type as well as other soft tissue tumor entities however is still poorly characterized. We analyzed SOX2 protein expression in soft tissue tumors. Alongside we tested Histone H3 expression (H3K27me3) in SOX2 positive cases to investigate this epigenetic mark and its correlation with the SOX2 status and clinicopathological parameters. MethodologyIn total, 60 samples of synovial sarcomas from the reference center for soft tissue tumors at the institute of pathology of the Jena University hospital were included into the study along with 343 other tissue tumors. Protein analysis was done by immunohistochemistry of tissue microarrays. All synovial sarcoma cases were confirmed by molecular testing using SS18 FISH break apart probes. ResultsSOX2 reactivity was detectable in 35 synovial sarcoma cases (58.3%) while 25 (41.7%) were negative. Only 13 cases of the other 343 soft tissue tumors, varying from nodular fasciitis to undifferentiated pleomorphic sarcoma, revealed a SOX2 expression, 12 out of these were undifferentiated high grade sarcoma. There was no obvious correlation with the clinicopathological data. H3K27me3 immunohistochemistry of the synovial sarcoma cases revealed a high statistically significant correlation between SOX2 and H3K27me3 expression (p < 0,0005, Chi square test). Similar to SOX2, there was no correlation between H3K27me3 expression and tumor grade. Six SOX2 positive synovial sarcoma cases were analyzed by FISH using a SOX2/CEN3 dual color FISH probe. None of these cases revealed an amplification of the SOX2 gene. ConclusionThe data confirms previous studies reporting SOX2 and H3K27me3 expression in synovial sarcoma and reveals that both biomarkers are related to each other. It strengthens the notion that the tumor type is driven by epigenetic processes similar to those that are operating in pluripotent stem cells. The relevance of these parameters in the pathway pathology of synovial sarcoma, i.e. the timing and dosing of SOX2 and H3K27me3 expression initiated by the SS18-SSX driver mutation together with the interplay of these events with other signaling pathways, cellular mechanisms and additional mutations in tumor progression, will require further studies.