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Diagnostics
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Molecular Classification of Soft Tissue and Bone Tumors
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Molecular Classification of Soft Tissue and Bone Tumors

A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 67857

Special Issue Editor

Prof. Dr. David Creytens

E-Mail Website
Guest Editor
Department of Pathology, Ghent University Hospital, 9000 Ghent, Belgium
Interests: surgical pathology; molecular pathology; genetics; immunohistochemistry; diagnostic and predictive biomarkers; soft tissue and bone tumors; sarcoma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Diagnostics is launching a Special Issue on “Molecular Classification of Soft Tissue and Bone Tumors”. Soft tissue and bone tumors constitute a very heterogeneous group of tumors containing >100 histological types and subtypes, which are diagnosed and classified using criteria from the World Health Organization (WHO). The considerable morphological overlap between the different diagnostic entities further adds to difficulties in classification. Overall, 50% of the entities listed in the fifth edition of WHO Classification of Tumours of Soft Tissue and Bone feature recurrent cytogenetic and/or molecular abnormalities. In classifying, the pathologist can be assisted by immunohistochemistry and molecular diagnostics. Immunohistochemistry is mostly used to confirm the line of differentiation, while molecular techniques (conventional cytogenetic analysis, fluorescence in situ hybridization (FISH) and cytogenomic array techniques, reverse transcription PCR (RT-PCR) and sequencing) can identify fusion genes resulting from recurrent chromosomal rearrangements (translocations) (such as SS18-SSX fusion in synovial sarcoma), recurrent patterns of imbalance like gene amplification (such as MDM2 amplification in atypical lipomatous tumor) or gene deletion (such as RB1 deletion in spindle cell/pleomorphic lipoma) or specific activating or inactivating mutations of certain genes (such as KIT in gastrointestinal stromal tumor (GIST) or SMARCB1 in malignant rhabdoid tumor, respectively).

On behalf of the Editorial Office, I would like to invite you to contribute your review articles and research papers concerning “Molecular Classification of Soft Tissue and Bone Tumors” for peer review and possible publication.

Prof. Dr. David Creytens
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Diagnostics is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Soft tissue and bone tumors
  • Histomorphology
  • Immunohistochemistry
  • Molecular based classification
  • Molecular pathology
  • Fluorescence in situ hybridization (FISH)
  • Sequencing
  • Gene fusions
  • Gene copy number variation

Published Papers (11 papers)

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Editorial

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3 pages, 162 KiB  
Editorial
Molecular Classification of Soft Tissue and Bone Tumors
by David Creytens
Diagnostics 2021, 11(12), 2326; https://doi.org/10.3390/diagnostics11122326 - 10 Dec 2021
Cited by 4 | Viewed by 1873
Abstract
Soft tissue and bone tumors constitute a large and heterogeneous group of tumors comprising >100 distinct histological types and subtypes, which are diagnosed and classified using criteria from the World Health Organization (WHO) Classification of Tumors [...] Full article
(This article belongs to the Special Issue Molecular Classification of Soft Tissue and Bone Tumors)

Research

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10 pages, 1781 KiB  
Article
Characterization of PD-1/PD-L1 Immune Checkpoint Expression in Osteosarcoma
by Kazuhiko Hashimoto, Shunji Nishimura and Masao Akagi
Diagnostics 2020, 10(8), 528; https://doi.org/10.3390/diagnostics10080528 - 29 Jul 2020
Cited by 18 | Viewed by 2672
Abstract
Recent data have suggested that PD-1 and PD-L1 are involved in osteosarcoma (OS) pathogenesis; however, their contributions are not well-established. Here, the PD-1/PD-L1 expression was evaluated in (OS) cases. Preoperative needle biopsy specimens were obtained from 16 patients with OS. Immunostaining for CD4, [...] Read more.
Recent data have suggested that PD-1 and PD-L1 are involved in osteosarcoma (OS) pathogenesis; however, their contributions are not well-established. Here, the PD-1/PD-L1 expression was evaluated in (OS) cases. Preoperative needle biopsy specimens were obtained from 16 patients with OS. Immunostaining for CD4, CD8, PD-1, and PD-L1 was performed on pathological specimens. Clinical parameters, including age, tumor size, preoperative alkaline phosphatase (ALP) level, standardized uptake value (SUV)-max level, and survival rate, were compared between PD-1/PD-L1-positive and -negative groups. CD4-, CD8-, PD-1-, and PD-L1-positive rates among all specimens were 75%, 75%, 18.7%, and 62.5%, respectively. The rates of co-expression of CD4 and CD8 with PD-L1 were 56.2% and 50%, respectively. Tumors were significantly larger in PD-L1-negative cases than in PD-L1-positive cases. Age, size and ALP and SUV-max levels did not differ significantly between PD-1/PD-L1-positive and -negative cases. The 3-year survival rates did not differ significantly between PD-1-positive and -negative cases or between PD-L1-positive and -negative cases. However, the occurrence of cancer-related events, including recurrence, metastasis, and death was associated with the PD-1-negative and PD-L1-positive status. The PD-1/PD-L1 checkpoint is likely involved in the immune microenvironment in OS and may be involved in the occurrence of cancer-related events. Full article
(This article belongs to the Special Issue Molecular Classification of Soft Tissue and Bone Tumors)
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Review

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41 pages, 12916 KiB  
Review
EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review
by Uta Flucke, Max M. van Noesel, Vasiliki Siozopoulou, David Creytens, Bastiaan B. J. Tops, Joost M. van Gorp and Laura S. Hiemcke-Jiwa
Diagnostics 2021, 11(6), 1093; https://doi.org/10.3390/diagnostics11061093 - 15 Jun 2021
Cited by 21 | Viewed by 6625
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Molecular Classification of Soft Tissue and Bone Tumors)
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20 pages, 15789 KiB  
Review
Diagnostic Immunohistochemistry of Soft Tissue and Bone Tumors: An Update on Biomarkers That Correlate with Molecular Alterations
by William J. Anderson and Vickie Y. Jo
Diagnostics 2021, 11(4), 690; https://doi.org/10.3390/diagnostics11040690 - 12 Apr 2021
Cited by 14 | Viewed by 8274
Abstract
The diagnosis of benign and malignant soft tissue and bone neoplasms is a challenging area of surgical pathology, due to the large number, rarity, and histologic diversity of tumor types. In recent years, diagnosis and classification has been aided substantially by our growing [...] Read more.
The diagnosis of benign and malignant soft tissue and bone neoplasms is a challenging area of surgical pathology, due to the large number, rarity, and histologic diversity of tumor types. In recent years, diagnosis and classification has been aided substantially by our growing understanding of recurrent molecular alterations in these neoplasms. Concurrently, the role of diagnostic immunohistochemistry has also expanded, with the development of numerous biomarkers based on underlying molecular events. Such biomarkers allow us to infer the presence of these events and can therefore substitute for other ancillary molecular genetic techniques (e.g., fluorescence in situ hybridization, polymerase chain reaction, and next-generation sequencing). In this review, we discuss a range of biomarkers currently available for these neoplasms, highlighting the accuracy, staining characteristics, and interpretation pitfalls of each antibody. These include immunohistochemical antibodies that represent reliable surrogates for the detection of gene fusions (e.g., STAT6, CAMTA1, FOSB, DDIT3) and more recently described breakpoint-specific antibodies (e.g., SS18-SSX, PAX3/7-FOXO1). Additionally, discussed are markers that correlate with the presence of gene amplifications (e.g., MDM2, CDK4), deletions (e.g., SMARCB1, SMARCA4), single nucleotide variants (e.g., G34W, K36M), aberrant methylation (H3K27me3), and increased expression as discovered through gene expression profiling (e.g., MUC4, DOG1, ETV4, NKX2.2, NKX3.1). Full article
(This article belongs to the Special Issue Molecular Classification of Soft Tissue and Bone Tumors)
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12 pages, 274 KiB  
Review
Translating Molecular Profiling of Soft Tissue Sarcomas into Daily Clinical Practice
by Celine Jacobs and Lore Lapeire
Diagnostics 2021, 11(3), 512; https://doi.org/10.3390/diagnostics11030512 - 14 Mar 2021
Cited by 3 | Viewed by 2007
Abstract
Soft tissue sarcomas are a group of rare mesenchymal tumors with more than 70 subtypes described. Treatment of these subtypes in an advanced setting is mainly according to a one-size-fits-all strategy indicating a high unmet need of new and more targeted therapeutic options [...] Read more.
Soft tissue sarcomas are a group of rare mesenchymal tumors with more than 70 subtypes described. Treatment of these subtypes in an advanced setting is mainly according to a one-size-fits-all strategy indicating a high unmet need of new and more targeted therapeutic options in order to optimize survival. The introduction of advanced molecular techniques in cancer has led to better diagnostics and identification of new therapeutic targets, leading to more personalized treatment and improved prognosis for several cancer types. In sarcoma, a likewise evolution is seen, albeit at a slower pace. This manuscript describes how in the past years advanced molecular profiling in soft tissue sarcomas was able to identify specific and often pathognomonic aberrations, deferring standard sarcoma treatment in favor of more targeted treatment from an oncologist’s point of view. Full article
(This article belongs to the Special Issue Molecular Classification of Soft Tissue and Bone Tumors)
15 pages, 8338 KiB  
Review
MDM2 Amplified Sarcomas: A Literature Review
by Raf Sciot
Diagnostics 2021, 11(3), 496; https://doi.org/10.3390/diagnostics11030496 - 11 Mar 2021
Cited by 45 | Viewed by 8717
Abstract
Murine Double Minute Clone 2, located at 12q15, is an oncogene that codes for an oncoprotein of which the association with p53 was discovered 30 years ago. The most important function of MDM2 is to control p53 activity; it is in fact the [...] Read more.
Murine Double Minute Clone 2, located at 12q15, is an oncogene that codes for an oncoprotein of which the association with p53 was discovered 30 years ago. The most important function of MDM2 is to control p53 activity; it is in fact the best documented negative regulator of p53. Mutations of the tumor suppressor gene p53 represent the most frequent genetic change in human cancers. By overexpressing MDM2, cancer cells have another means to block p53. The sarcomas in which MDM2 amplification is a hallmark are well-differentiated liposarcoma/atypical lipomatous tumor, dedifferentiated liposarcoma, intimal sarcoma, and low-grade osteosarcoma. The purpose of this review is to summarize the typical clinical, histopathological, immunohistochemical, and genetic features of these tumors. Full article
(This article belongs to the Special Issue Molecular Classification of Soft Tissue and Bone Tumors)
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15 pages, 1340 KiB  
Review
NTRK Fusions in Sarcomas: Diagnostic Challenges and Clinical Aspects
by Vasiliki Siozopoulou, Evelien Smits, Koen De Winne, Elly Marcq and Patrick Pauwels
Diagnostics 2021, 11(3), 478; https://doi.org/10.3390/diagnostics11030478 - 09 Mar 2021
Cited by 28 | Viewed by 3914
Abstract
Tropomyosin receptor kinase (TK) is encoded by the neurotrophic tyrosine receptor kinase genes (NTRK) 1, 2, and 3, whose activation plays an important role in cell cycle proliferation and survival. Fusions of one of these genes can lead to constitutive activation [...] Read more.
Tropomyosin receptor kinase (TK) is encoded by the neurotrophic tyrosine receptor kinase genes (NTRK) 1, 2, and 3, whose activation plays an important role in cell cycle proliferation and survival. Fusions of one of these genes can lead to constitutive activation of TRK, which can potentially be oncogenic. NTRK fusions are commonly present in rare histologic tumor types. Among sarcomas, infantile fibrosarcoma shows NTRK fusion in more than 90% of the cases. Many other sarcoma types are also investigated for NTRK fusions. These fusions are druggable alteration of the agnostic type, meaning that all NTRK fused tumors can be treated with NTRK-inhibitors regardless of tumor type or tissue of origin. TRK-inhibitors have shown good response rates, with durable effects and limited side effects. Resistance to therapy will eventually occur in some cases, wherefore the next-generation TRK-inhibitors are introduced. The diagnosis of NTRK fused tumors, among them sarcomas, remains an issue, as many algorithms but no guidelines exist to date. Given the importance of this diagnosis, in this paper we aim to (1) analyze the histopathological features of sarcomas that correlate more often with NTRK fusions, (2) give an overview of the TRK-inhibitors and the problems that arise from resistance to the therapy, and (3) discuss the diagnostic algorithms of NTRK fused tumors with emphasis on sarcomas. Full article
(This article belongs to the Special Issue Molecular Classification of Soft Tissue and Bone Tumors)
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18 pages, 10220 KiB  
Review
The Rapidly Expanding Group of RB1-Deleted Soft Tissue Tumors: An Updated Review
by Sasha Libbrecht, Jo Van Dorpe and David Creytens
Diagnostics 2021, 11(3), 430; https://doi.org/10.3390/diagnostics11030430 - 03 Mar 2021
Cited by 21 | Viewed by 7800
Abstract
The classification of soft tissue tumors has evolved considerably in the last decade, largely due to advances in understanding the pathogenetic basis of many of these, sometimes rare, tumors. Deletion of Retinoblastoma 1 (RB1), a well-known tumor suppressor gene, has been [...] Read more.
The classification of soft tissue tumors has evolved considerably in the last decade, largely due to advances in understanding the pathogenetic basis of many of these, sometimes rare, tumors. Deletion of Retinoblastoma 1 (RB1), a well-known tumor suppressor gene, has been implicated in the tumorigenesis of a particular group of soft tissue neoplasms. This group of so-called “RB1-deleted soft tissue tumors” has been rapidly expanding in recent years, currently consisting of spindle cell/pleomorphic lipoma, atypical spindle cell/pleomorphic lipomatous tumor, pleomorphic liposarcoma, myofibroblastoma, cellular angiofibroma, and acral fibromyxoma. Most of these neoplasms, except pleomorphic liposarcoma, are considered benign entities and are mainly described in the older adult population. This article will review the currently known morphological, immunohistochemical, and molecular features of this heterogeneous group of mesenchymal tumors with an emphasis on differential diagnosis. Full article
(This article belongs to the Special Issue Molecular Classification of Soft Tissue and Bone Tumors)
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19 pages, 5734 KiB  
Review
Update on Endometrial Stromal Tumours of the Uterus
by Iolia Akaev, Chit Cheng Yeoh and Siavash Rahimi
Diagnostics 2021, 11(3), 429; https://doi.org/10.3390/diagnostics11030429 - 03 Mar 2021
Cited by 24 | Viewed by 7562
Abstract
Endometrial stromal tumours (ESTs) are rare, intriguing uterine mesenchymal neoplasms with variegated histopathological, immunohistochemical and molecular characteristics. Morphologically, ESTs resemble endometrial stromal cells in the proliferative phase of the menstrual cycle. In 1966 Norris and Taylor classified ESTs into benign and malignant categories [...] Read more.
Endometrial stromal tumours (ESTs) are rare, intriguing uterine mesenchymal neoplasms with variegated histopathological, immunohistochemical and molecular characteristics. Morphologically, ESTs resemble endometrial stromal cells in the proliferative phase of the menstrual cycle. In 1966 Norris and Taylor classified ESTs into benign and malignant categories according to the mitotic count. In the most recent classification by the WHO (2020), ESTs have been divided into four categories: Endometrial Stromal Nodules (ESNs), Low-Grade Endometrial Stromal Sarcomas (LG-ESSs), High-Grade Endometrial Stromal Sarcomas (HG-ESSs) and Undifferentiated Uterine Sarcomas (UUSs). ESNs are clinically benign. LG-ESSs are tumours of low malignant potential, often with indolent clinical behaviour, with some cases presented with a late recurrence after hysterectomy. HG-ESSs are tumours of high malignant potential with more aggressive clinical outcome. UUSs show high-grade morphological features with very aggressive clinical behavior. With the advent of molecular techniques, the morphological classification of ESTs can be integrated with molecular findings in enhanced classification of these tumours. In the future, the morphological and immunohistochemical features correlated with molecular categorisation of ESTs, will become a robust means to plan therapeutic decisions, especially in recurrences and metastatic disease. In this review, we summarise the morphological, immunohistochemical and molecular features of ESTs with particular reference to the most recent molecular findings. Full article
(This article belongs to the Special Issue Molecular Classification of Soft Tissue and Bone Tumors)
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23 pages, 5544 KiB  
Review
Update on Molecular Genetics of Gastrointestinal Stromal Tumors
by Iva Brčić, Alexandra Argyropoulos and Bernadette Liegl-Atzwanger
Diagnostics 2021, 11(2), 194; https://doi.org/10.3390/diagnostics11020194 - 28 Jan 2021
Cited by 35 | Viewed by 5288
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The majority are sporadic, solitary tumors that harbor mutually exclusive KIT or PDGFRA gain-of-function mutations. The type of mutation in addition to risk stratification corresponds to the biological behavior [...] Read more.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The majority are sporadic, solitary tumors that harbor mutually exclusive KIT or PDGFRA gain-of-function mutations. The type of mutation in addition to risk stratification corresponds to the biological behavior of GIST and response to treatment. Up to 85% of pediatric GISTs and 10–15% of adult GISTs are devoid of these (KIT/PDGFRA) mutations and are referred to as wild-type GISTs (wt-GIST). It has been shown that these wt-GISTs are a heterogeneous tumor group with regard to their clinical behavior and molecular profile. Recent advances in molecular pathology helped to further sub-classify the so-called “wt-GISTs”. Based on their significant clinical and molecular heterogeneity, wt-GISTs are divided into a syndromic and a non-syndromic (sporadic) subgroup. Recently, the use of succinate dehydrogenase B (SDHB) by immunohistochemistry has been used to stratify GIST into an SDHB-retained and an SDHB-deficient group. In this review, we focus on GIST sub-classification based on clinicopathologic, and molecular findings and discuss the known and yet emerging prognostic and predictive genetic alterations. We also give insights into the limitations of targeted therapy and highlight the mechanisms of secondary resistance. Full article
(This article belongs to the Special Issue Molecular Classification of Soft Tissue and Bone Tumors)
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33 pages, 6437 KiB  
Review
Retroperitoneal Sarcomas: An Update on the Diagnostic Pathology Approach
by Joon Hyuk Choi and Jae Y. Ro
Diagnostics 2020, 10(9), 642; https://doi.org/10.3390/diagnostics10090642 - 27 Aug 2020
Cited by 25 | Viewed by 11687
Abstract
Retroperitoneal sarcomas are a heterogenous group of rare tumors arising in the retroperitoneum. Retroperitoneal sarcomas comprise approximately 10% of all soft tissue sarcomas. Though any soft tissue sarcoma histologic types may arise in the retroperitoneal space, liposarcoma (especially well-differentiated and dedifferentiated types) and [...] Read more.
Retroperitoneal sarcomas are a heterogenous group of rare tumors arising in the retroperitoneum. Retroperitoneal sarcomas comprise approximately 10% of all soft tissue sarcomas. Though any soft tissue sarcoma histologic types may arise in the retroperitoneal space, liposarcoma (especially well-differentiated and dedifferentiated types) and leiomyosarcoma do so most commonly. Retroperitoneal sarcomas are diagnostically challenging, owing to their diversity and morphological overlap with other tumors arising in the retroperitoneum. An accurate diagnosis is necessary for correct management and prognostication. Herein, we provide an update on the diagnostic approach to retroperitoneal sarcomas and review their key histologic findings and differential diagnoses. Full article
(This article belongs to the Special Issue Molecular Classification of Soft Tissue and Bone Tumors)
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