Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Low-grade central fibroblastic osteosarcoma may be differentiated from its mimicker desmoplastic fibroma by genetic analysis

Low-grade central fibroblastic osteosarcoma may be differentiated from its mimicker desmoplastic... Background: We studied two cases of rare fibrous bone tumors, namely desmoplastic fibroma (DF) and low ‑ grade central osteosarcoma (LGCOS) resembling desmoplastic fibroma (DF ‑ like LGCOS). As the clinical presentation, imaging features and histopathology of DF and DF‑ like LGOS show much overlap, the objective of this study was to investigate the value of cytogenetic analysis, molecular pathology and immunohistochemistry in discrimination of these two mimickers. Case presentation: A mutation in CTNNB (S45F) and nuclear beta‑ catenin immunostaining were observed in DF. DF‑ LGCOS had amplification of CDK4 and showed strong nuclear expression of CDK4 by IHC. Moreover, the karyotype of DF‑ LGCOS showed an interstitial heterozygous deletion of the long arm of chromosome 13 (q12q32), associated with loss of the RB1 tumor suppressor gene. Conclusions: Karyotyping and molecular genetic analysis may contribute to a conclusive diagnosis. Keywords: Bone sarcoma, Desmoplastic fibroma, Low ‑ grade osteosarcoma, CDK4, RB1 Background gene translocations to differentiate Ewing sarcoma from The histopathological diagnosis of bone tumors is usu - other round cell sarcomas, and detection of H3F3A muta- ally rather straightforward, since the most common bone tions to accurately diagnose giant cell tumor of bone. tumors show differentiation along osteoblastic or chond - However, for fibrous tumors of bone the incremental roblastic lines, and form bone matrix or cartilage, which value of IHC and DNA methods over standard basic his- usually can be easily detected in routinely stained tissue tology is rather limited. This category of fibrous tumors sections. of bone includes the desmoplastic fibroma (DF)—a rare, In the past decades, advances in the field of immuno - locally aggressive tumor—and fibrosarcoma—a tumor histochemistry (IHC) and molecular pathology have once considered to be very common, but currently a allowed a precise diagnosis in difficult cases. Examples diagnosis of exclusion, that one is only allowed to make are IHC for SATB2 to confirm a tentative diagnosis of after having ruled out other spindle cell tumors, e.g. low osteosarcoma, molecular DNA analysis for nonrandom grade myofibroblastic sarcoma, myoepithelial tumors, follicular dendritic cell tumors, synovial sarcoma, and, last but not least, a rare variant of low-grade central oste- *Correspondence: a.j.h.suurmeijer@umcg.nl osarcoma (LGCOS) resembling desmoplastic fibroma Department of Pathology and Medical Biology, University Medical (DF-like LGCOS). Center Groningen, University of Groningen, P.O. Box 30.001, 9700 By co-incidence, two patients with these rare bone RB Groningen, The Netherlands Full list of author information is available at the end of the article tumors (DF and DF-LGCOS) were treated in our © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Song et al. Clin Sarcoma Res (2018) 8:16 Page 2 of 8 sarcoma center in the same week. In addition to IHC, we 12 × 4 cm. On cut surface the tumor was pale and fibrous. decided to apply classic cytogenetics and next generation There was extension to surrounding soft tissue (Fig. 3b). sequencing (NGS), which proved to be very helpful in Tumor histology strongly resembled the desmoplastic discriminating these two morphologic mimickers. fibroma diagnosed in case 1, however, with some differ - ences. As shown in Fig.  4a, this tumor also consisted of bundles of moderate cellular tissue, with fibroblast-like, Case presentation spindle cells in abundant collagenous stroma. However, Case 1: a 10-year-old girl, with a history of distal radius there was evidence of invasive growth in trabecular bone fracture 3 years earlier, presented with a firm, nontender and surrounding skeletal muscle tissue. Although nuclear swelling in the same right distal forearm. Her wrist func- chromatin was bland, few normal mitoses were found. tion was unimpaired. As shown in Fig.  1, X-ray exami- Osteoid or trabecular bone was absent. nation revealed a large lobulated, compartmentalized, As depicted in Fig.  4b, cytogenetic analysis showed osteolytic, expansive tumor mass in the metadiaphy- an abnormal karyotype: 47~49,XX,del(13) (q12q32),+ sis of the distal radius. On MRI, the tumor measured 1~2r,+1~2mar,1dmin [cp17]/46,XX [2]. This encom - 35 × 46 × 47  mm and had a well-defined boundary, but passes an interstitial deletion of the long arm of chro- no sclerotic margin. Starting from the distal radius, mosome 13 (q12q32), consistent with heterozygous there was cortical destruction, an extensive soft tissue loss of the RB1 tumor suppressor gene. With cancer component, and impression and bowing of the distal hotspot NGS analysis we found amplification of CDK4 ulna. There were no imaging signs of invasive growth, (NM_000075.3) and an imbalance of the RB1 gene on necrosis or fluid-liquid mirrors. Bone scintigraphy did chromosome 13. not show increased uptake at the location of the lesion. With IHC, tumor cells exhibited strong nuclear stain- These imaging features were consistent with a destructive ing for CDK4 (Fig. 4c) and moderate nuclear staining for tumor that originated from the distal radius, grew slowly, SATB2. RB1 expression was heterogeneous, not com- and then broke through the cortex of the radius into pletely lost. the adjacent soft tissue. The tumor was excised intral - In this case a conclusive diagnosis of DF-LGOS could esionally. Grossly, the largest tumor fragment measured be made, based on histologic features (an invasive fibro - 6 × 5 × 3  cm. On cut surface the tumor tissue was pale blastic tumor with mitotic activity), karyotyping (het- and fibrous. erozygous loss of RB1) and molecular genetics/IHC Tumor histology was reminiscent of desmoid fibroma - (CDK4 amplification). tosis and consistent with desmoplastic fibroma, as it showed a lesion composed of bundles of moderately cel- lular, collagenous tumor tissue with fibroblastic spindle Discussion and conclusions cells with oval, monomorphic nuclei with bland, finely We have presented the clinical presentation, imaging granular chromatin, small nucleoli and ample cytoplasm. studies, gross and microscopic pathology, IHC, cytoge- Mitoses were not found (Fig. 2a). netics and molecular genetics (cancer hotspot analysis) Cytogenetic analysis revealed a normal female kar- of DF and DF-LCOS, two very rare bone tumors, which yotype in 18 cells, with trisomy 8 detected in 2 cells closely resemble each other. (Fig. 2b). DF is very rare indeed. Among 4692 benign bone The cancer hotspot NGS analysis revealed a CTNNB1 tumors treated in the Birmingham Royal Orthopedic hotspot class 5 pathogenic variant in exon 3: p.Ser45Phe Hospital, Evans et  al. [1] identified 13 cases of DF, an and, using IHC, the fibroblastic tumor cells showed more incidence of 0.003%. Böhm et  al. [2] reviewed 189 cases than focal nuclear staining for beta-catenin (Fig.  2c), in of DF reported in the literature up to 1996 and observed support of a diagnosis of desmoplastic fibroma. that, although DF occurs at all ages, children and young Case 2: a 24-year-old woman presented with pro- adults are most commonly affected, three-quarter of gressive pain in the right hip region that had existed patients being younger than 31 years. Sex distribution is for 1  year. X-ray images showed an osteolytic tumor in almost equal. DF most commonly presents in the man- the metadiaphysis of the right distal femur with corti- dible (22%), but also in pelvic bones (13%), and long cal bone destruction on the dorsolateral side. The cen - bones—femur (15%), radius (12%), and tibia (9%). Nota- tral part of the tumor had no matrix calcification. On bly, pathologic fracture of a long bone was reported in MRI, the tumor destroyed the cortex and extended to 12% of patients. Thus, the clinical presentation of our the surrounding soft tissues. There was strong tumor DF case as a tumor in the distal radius of a 10-year-old enhancement after administration of intravenous gado- girl, who had experienced a radius fracture 3 years earlier, linium (Fig.  3a). A resection of the right distal femur matches data from the literature. was performed. The tumor in the distal femur measured Song et al. Clin Sarcoma Res (2018) 8:16 Page 3 of 8 Fig. 1 Conventional AP and lateral radiographs (top left and top middle) show an expansive bubbly lytic bone lesion in the diaphysis‑metaphysis of the right distal radius with a narrow zone of transition, nonsclerotic margins, cortical thinning and destruction, and an accompanying large soft‑tissue mass which appears to compress the distal ulna with bowing of the latter. Bone scintigraphy (top right) shows no increased uptake at the location of the lesion. MRI with coronal T1‑ weighted (bottom left) and gadolinium‑ enhanced T1‑ weighted (bottom middle) images, and axial T2‑ weighted and gadolinium‑ enhanced fat‑suppressed T1‑ weighted images (bottom right) are in keeping with the conventional radiographic findings, and also demonstrate no signs of invasion in surrounding muscles or ulna. Remarkably, in the center of the lesion there is low signal on all sequences (arrows), most strikingly on the T2‑ weighted sequence. Because the combined imaging features suggest a slow‑ growing (most likely benign) process with fibrotic components, the differential diagnostic considerations include desmoplastic fibroma, and (less likely) giant ‑ cell tumor or fibrous dysplasia Song et al. Clin Sarcoma Res (2018) 8:16 Page 4 of 8 Fig. 2 Histology, karyotype and beta‑ catenin nuclear expression in DF. a Histology showing a fibroblastic tumor with little or no nuclear atypia or mitotic activity (H&E, original magnification × 200). As such, the histology of DF resembles that DF‑LGCOS shown in Fig. 4a. b DF karyotype: 47,XX,+8[2]/46,XX[18]. c IHC expression of beta‑ catenin in several tumor cell nuclei of DF (original magnification × 400) It is well appreciated that DF has a high recurrence rate Moreover, infiltrative tumor growth may be seen by after intralesional excision [1, 2], but since DF is a benign microscopy. Mitoses are only rarely found, an important tumor that does not metastasize, we choose to remove criterion to discriminate DF from DF-LCOS or low-grade the radius tumor of this young girl intralesionally, in fibrosarcoma [4]. order to preserve arm and wrist function. Unfortunately, Cytogenetic analysis of our DF case revealed a normal a recurrence has occurred 12 months after surgery. female karyotype in 18 cells, with a trisomy 8 detected As our case illustrates, DF may present as a slowly pro- in 2 cells. To our knowledge, only two papers have been gressive but locally aggressive tumor. As reviewed by published on the cytogenetics and molecular genetics of Nedopil et  al. [3] by imaging studies, DF can show cor- DF. Bridge et  al. [5] found trisomies 8 and 20 in a single tical breakthrough and extension in surrounding soft case of DF, but again, these cytogenetic abnormalities tissue. were also detected in other fibro-osseous bone tumors, Song et al. Clin Sarcoma Res (2018) 8:16 Page 5 of 8 Fig. 3 Conventional AP, lateral radiographs and gross morphology of DF‑LGCOS. a Conventional AP, lateral radiographs (top left and top middle) show an expansive osteolytic lesion in the diaphysis‑metaphysis of the right distal femur with an ill‑ defined border and cortical destruction. Bone scintigraphy (top right) demonstrates increased uptake at the location of the lesion, but no suspicious uptake elsewhere. MRI with sagittal T1‑ weighted (bottom left) and fat‑suppressed proton density‑ weighted (bottom middle) images, and axial T1‑ weighted and gadolinium‑ enhanced fat‑suppressed T1‑ weighted images (bottom right) show the T1 hypointense, T2 hyperintense, and vividly enhancing lesion in the right distal femur as a large soft‑tissue mass with cortical breakthrough and extra‑ osseous expansion. The combined imaging features are highly suggestive of an aggressive malignant lesion, with osteosarcoma, Ewing sarcoma, and chondrosarcoma being the main differential diagnostic considerations. b Gross specimen of DF‑LGCOS, showing a white, fibrous tumor of the distal femur with cortical breakthrough and invasion of soft tissue. As such, the gross appearance of DF‑LGCOS resembles DF by which these are noncontributory to a certain DF tumors [9] or fibrous soft tissue tumors [12]. Moreover, diagnosis. IHC for beta-catenin is not specific for APC/CTNNB1 An abnormal karyotype 46,XX,del(11)(q13q23),der(19) mutations in fibro-osseous bone tumors. CTNNB1 muta - t(11;19)(q13;p13)del(11)(q23) was reported by Trombetta tions are a rare molecular event in the few cases of DF et al. [6] in a DF occurring in the femur of a 20-year-old that have been analyzed [7–9]. In fact, Flucke et  al. [8] female patient. It was hypothesized that loss of a genomic found a p.T41A CTNNB1 mutation in 1 out of 2 cases of region in 11q, an area containing the genes RBM14, DF arising in the mandible, Horvai and Jordan [9] found RBM4, RBM4B, SPTBN2, and C11orf80 may be of patho- an APC mutation, but no CTNNB1 mutation in a single genic significance. DF analyzed, and Hauben et  al. [7] found no CTNNB1 Using IHC, others and we have noticed nuclear stain- mutation in six DF cases. Using NGS, we detected a ing of beta-catenin in DF [3, 4, 7–11]. However, although CTNNB1 hotspot class 5 pathogenic variant in exon 3: nuclear expression of beta-catenin supports a diagnosis p.S45F, which is a gain of function mutation. Clearly, to of DF, one has to be aware that nuclear immunostaining be able to estimate the real frequency of CTNNB1 muta- of beta-catenin also occurs in other fibro-osseous bone tions in DF, more cases have to be studied, preferably Song et al. Clin Sarcoma Res (2018) 8:16 Page 6 of 8 Fig. 4 Histology, karyotype and CDK4 expression in DF‑LGOS. a Histology showing a fibroblastic tumor with permeative invasive growth (H&E, original magnification × 100). As such, the histology of DF‑LGCOS resembles that of DF, shown in Fig. 2a. b DF‑LGOS karyotype: 47~49,XX,del(13) (q12q32),+1~2r,+1~2mar,1dmin[cp17]/46,XX[2]. c Diffuse nuclear expression of CDK4 in cell nuclei of DF‑LGCOS (original magnification × 200) using NGS, since NGS has a higher sensitivity compared tumor that had invaded bone. However, given the imag- with traditional DNA sequencing methods in picking up ing features, in particular the bubbly compartmental- CTNNB1 mutations [13] Interestingly, the S45F CTNNB ized appearance of the radius tumor and the bowing of mutation also occurs in desmoid fibromatosis, in particu - the distal ulna without bone invasion (see Fig.  1), we lar in aggressive and recurrent lesions [14]. However, it regarded the radius tumor in this girl as a slow growing remains to be proven that DF is the bony counterpart of primary bone tumor with soft tissue extension, a clinical desmoid fibromatosis of soft tissue. In this respect, one presentation consistent with a histopathologic diagnosis may argue whether our case 1 represents a soft tissue of desmoplastic fibroma of bone. Song et al. Clin Sarcoma Res (2018) 8:16 Page 7 of 8 The majority of central osteosarcomas are high- DF. Both are fibrous tumors of bone with are slowly grade conventional osteosarcomas, in which the tumor progressive and locally aggressive showing cortical cells show severe nuclear atypia and produce a variable breakthrough. DF and DF-LGCOS consist of bundles of amount of cartilaginous or osteoid matrix. High grade moderately cellular collagenous tumor tissue with spin- osteosarcomas with severe nuclear atypia, but little or no dled fibroblast-like cells. The two cases reported herein matrix formation can be confirmed by SATB2 immuno - show that karyotyping and molecular genetic analysis histochemistry [15, 16]. may contribute to a conclusive diagnosis, DF show- Our DF-LGCOS case is part of another subset of low ing CTNNB1 S45F mutation and DF-LGCOS showing grade central osteosarcomas namely the ones that resem- CDK4 amplification. ble DF and have little or no osteoid matrix deposition. So far, this very rare OS subtype has only been described in Abbreviations case reports and small series [17, 18]. Most likely these DF: desmoplastic fibroma; DF‑like LGCOS: low‑ grade central osteosarcoma rare DF-LCOS have been included in the histological (LGCOS) resembling desmoplastic fibroma; NGS: next generation sequencing; IHC: immunohistochemistry; LGCOS: low‑ grade central osteosarcoma; CC1: spectrum of fibrosarcomas of bone [4]. We agree with cell conditioning buffer 1. Horvai and Jordan [9], who stated that it seems logical that at least a subset of fibrosarcomas of bone are actu - Authors’ contributions WS observed pathology specimens, participated in the study design and ally osteosarcomas with little or no osteoid or bone for- drafted the manuscript. EB and AMCJ performed classic cytogenetics and next mation. Surprisingly, in the 2013 WHO classification of generation sequencing, respectively. TCK interpreted imaging features. PCJ tumors of soft tissue and bone, fibrosarcomas of bone are performed the surgery, managed the patient and completed the clinical data collection. JVMGB conceived of the study, participated in its design. AJS con‑ defined as intermediate to high grade spindle cell tumors ceived, designed and supervised this article. All authors read and approved that lack any line of differentiation other than fibroblas - the final manuscript. tic, leaving little room for the recognition of low grade Author details variants, also excluding DF- LGCOS. Department of Pathology and Medical Biology, University Medical Center Strong and diffuse SATB2 nuclear IHC staining reflects Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The an osteoblastic line of differentiation. To date, only one Netherlands. Department of Genetics, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Nether‑ Chinese study investigated SATB2 expression in low lands. Department of Radiology, Nuclear Medicine and Molecular Imaging, grade osteosarcoma and desmoplastic fibroma. These University Medical Center Groningen, University of Groningen, P.O. Box 30.001, authors found that low-grade osteosarcoma and fibrous 9700 RB Groningen, The Netherlands. Department of Orthopedic Surgery, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, dysplasia are positive for SATB2, while desmoplas- 9700 RB Groningen, The Netherlands. Department of Pathology, Leiden tic fibroma, low-grade fibrosarcoma and other fibrous University Medical Center, Leiden, The Netherlands. tumors are negative [19]. Acknowledgements The notion that DF-LGCOS is an osteosarcoma vari - We want to acknowledge Tom van Wezel and Dina Ruano Neto (Pathology, ant is also supported by the cytogenetics and molecular LUMC) for setting up the NGS pipeline. genetics of our second case. DF-LGCOS had a karyotype Competing interests with interstitial deletion of the long arm of chromosome The authors declare that they have no competing interests. 13 (q12q32), consistent with loss of the RB1 tumor sup- pressor gene, a genetic abnormality found in a substantial Availability of data and materials The dataset supporting the conclusions of this article is included within the number of osteosarcomas. Notably, cancer hotspot NGS article. analysis revealed amplification of CDK4 and IHC showed overexpression of CDK4. Consent for publication Written informed consent for publication of their clinical details and/or clinical The prototypical LGCOS (which resembles parosteal images was obtained from the patient. A copy of the consent form is available osteosarcoma) usually produces abundant bone matrix for review by the Editor of this journal. and contains trabecular woven bone. The fibroblas - Ethics approval and consent to participate tic stromal cells of the prototypical LGCOS show slight All procedures performed in studies involving human participants were in nuclear atypia and mitosis are not easily discerned. This accordance with the ethical standards of the institutional and/or national subset of LGCOS often has gain or amplification of the research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study met the criteria of MDM2 and/or CDK4 genes, which can be visualized by the code of conduct for responsible use of human tissue that is used in the their nuclear expression by IHC [19]. By IHC, CDK4 is Netherlands (Dutch federation of biomedical scientific societies; http://www. positive in the majority of LGOS, and, when combined feder a.org). with MDM2 immunostaining, the sensitivity and speci- Funding ficity for LGOS is 100% and 97.5%, respectively [20]. Wangzhao Song receives funding from the China Scholarship Council (CSC) The clinical presentation, imaging studies and gross program (Grant No: 201606940023). morphology of DF-LGCOS shows much overlap with Song et al. Clin Sarcoma Res (2018) 8:16 Page 8 of 8 10. Woods TR, Cohen DM, Islam MN, et al. Desmoplastic fibroma of the man‑ Publisher’s Note dible: a series of three cases and review of literature. Head Neck Pathol. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 2015;9:196–204. lished maps and institutional affiliations. 11. Okubo T, Saito T, Takagi T, et al. Desmoplastic fibroma of the rib with cystic change: a case report and literature review. Skeletal Radiol. Received: 18 May 2018 Accepted: 23 July 2018 2014;43:703–8. 12. Carlson JW, Fletcher CD. Immunohistochemistry for beta‑ catenin in the differential diagnosis of spindle cell lesions: analysis of a series and review of the literature. Histopathology. 2007;51:509–14. 13. Colombo C, Urbini M, Astolfi A, et al. Novel intra‑ genic large deletions References of CTNNB1 gene identified in WT desmoid‑type fibromatosis. Genes 1. Evans S, Ramasamy A, Jeys L, et al. Desmoplastic fibroma of bone: a rare Chromosomes Cancer. 2018. https ://doi.org/10.1002/gcc.22644 . bone tumour. J Bone Oncol. 2014;3:77–9. 14. van Broekhoven DL, Verhoef C, Grünhagen D, et al. Prognostic value of 2. Bohm P, Krober S, Greschniok A, et al. Desmoplastic fibroma of the bone. CTNNB1 gene mutation in primary sporadic aggressive fibromatosis. Ann A report of two patients, review of the literature, and therapeutic implica‑ Surg Oncol. 2015;22:1464–70. tions. Cancer. 1996;78:1011–23. 15. Conner JR, Hornick JL. SATB2 is a novel marker of osteoblastic differentia‑ 3. Nedopil A, Raab P, Rudert M. Desmoplastic fibroma: a case report with tion in bone and soft tissue tumours. Histopathology. 2013;63:36–49. three years of clinical and radiological observation and review of the 16. Davis JL, Horvai AE. Special AT‑rich sequence ‑binding protein 2 (SATB2) literature. Open Orthop J. 2013;8:40–6. expression is sensitive but may not be specific for osteosarcoma as com‑ 4. Saito T, Oda Y, Tanaka K, et al. Low‑ grade fibrosarcoma of the proximal pared with other high‑ grade primary bone sarcomas. Histopathology. humerus. Pathol Int. 2003;53:115–20. 2016;69:84–90. 5. Bridge JA, Swarts SJ, Buresh C, et al. Trisomies 8 and 20 characterize a 17. Kurt AM, Unni KK, McLeod RA, et al. Low‑ grade intraosseous osteosar‑ subgroup of benign fibrous lesions arising in both soft tissue and bone. coma. Cancer. 1990;65:1418–28. Am J Pathol. 1999;154:729–33. 18. Bertoni F, Bacchini P, Fabbri N, et al. Osteosarcoma. Low‑ grade 6. Trombetta D, Macchia G, Mandahl N, et al. Molecular genetic charac‑ intraosseous‑type osteosarcoma, histologically resembling parosteal terization of the 11q13 breakpoint in a desmoplastic fibroma of bone. osteosarcoma, fibrous dysplasia, and desmoplastic fibroma. Cancer. Cancer Genet. 2012;205:410–3. 1993;71:338–45. 7. Hauben E, Jundt G, Cleton‑ Jansen AM, et al. Desmoplastic fibroma of 19. Chen CY, Zhang HZ, Jiang ZM, et al. Value of MDM2, CDK4 and SATB2 bone: an immunohistochemical study including beta‑ catenin expression immunohistochemistry in histologic diagnosis of low‑ grade osteosar‑ and mutational analysis for beta‑ catenin. Hum Pathol. 2005;36:1025–30. coma. Zhonghua Bing Li Xue Za Zhi. 2016;45:387–92. 8. Flucke U, Tops BB, van Diest PJ, et al. Desmoid‑type fibromatosis of the 20. Yoshida A, Ushiku T, Motoi T, et al. Immunohistochemical analysis of head and neck region in the paediatric population: a clinicopathological MDM2 and CDK4 distinguishes low‑ grade osteosarcoma from benign and genetic study of seven cases. Histopathology. 2014;64:769–76. mimics. Mod Pathol. 2010;23:1279–88. 9. Horvai A, Jordan R. Fibro‑ osseous lesions of the craniofacial bones: β‑ catenin immunohistochemical analysis and CTNNB1 and APC mutation analysis. Head Neck Pathol. 2014;8(3):291–7. Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

Low-grade central fibroblastic osteosarcoma may be differentiated from its mimicker desmoplastic fibroma by genetic analysis

Loading next page...
 
/lp/springer-journals/low-grade-central-fibroblastic-osteosarcoma-may-be-differentiated-from-qFuRMfnPTs

References (23)

Publisher
Springer Journals
Copyright
Copyright © 2018 by The Author(s)
Subject
Biomedicine; Cancer Research; Oncology; Surgical Oncology
eISSN
2045-3329
DOI
10.1186/s13569-018-0104-z
Publisher site
See Article on Publisher Site

Abstract

Background: We studied two cases of rare fibrous bone tumors, namely desmoplastic fibroma (DF) and low ‑ grade central osteosarcoma (LGCOS) resembling desmoplastic fibroma (DF ‑ like LGCOS). As the clinical presentation, imaging features and histopathology of DF and DF‑ like LGOS show much overlap, the objective of this study was to investigate the value of cytogenetic analysis, molecular pathology and immunohistochemistry in discrimination of these two mimickers. Case presentation: A mutation in CTNNB (S45F) and nuclear beta‑ catenin immunostaining were observed in DF. DF‑ LGCOS had amplification of CDK4 and showed strong nuclear expression of CDK4 by IHC. Moreover, the karyotype of DF‑ LGCOS showed an interstitial heterozygous deletion of the long arm of chromosome 13 (q12q32), associated with loss of the RB1 tumor suppressor gene. Conclusions: Karyotyping and molecular genetic analysis may contribute to a conclusive diagnosis. Keywords: Bone sarcoma, Desmoplastic fibroma, Low ‑ grade osteosarcoma, CDK4, RB1 Background gene translocations to differentiate Ewing sarcoma from The histopathological diagnosis of bone tumors is usu - other round cell sarcomas, and detection of H3F3A muta- ally rather straightforward, since the most common bone tions to accurately diagnose giant cell tumor of bone. tumors show differentiation along osteoblastic or chond - However, for fibrous tumors of bone the incremental roblastic lines, and form bone matrix or cartilage, which value of IHC and DNA methods over standard basic his- usually can be easily detected in routinely stained tissue tology is rather limited. This category of fibrous tumors sections. of bone includes the desmoplastic fibroma (DF)—a rare, In the past decades, advances in the field of immuno - locally aggressive tumor—and fibrosarcoma—a tumor histochemistry (IHC) and molecular pathology have once considered to be very common, but currently a allowed a precise diagnosis in difficult cases. Examples diagnosis of exclusion, that one is only allowed to make are IHC for SATB2 to confirm a tentative diagnosis of after having ruled out other spindle cell tumors, e.g. low osteosarcoma, molecular DNA analysis for nonrandom grade myofibroblastic sarcoma, myoepithelial tumors, follicular dendritic cell tumors, synovial sarcoma, and, last but not least, a rare variant of low-grade central oste- *Correspondence: a.j.h.suurmeijer@umcg.nl osarcoma (LGCOS) resembling desmoplastic fibroma Department of Pathology and Medical Biology, University Medical (DF-like LGCOS). Center Groningen, University of Groningen, P.O. Box 30.001, 9700 By co-incidence, two patients with these rare bone RB Groningen, The Netherlands Full list of author information is available at the end of the article tumors (DF and DF-LGCOS) were treated in our © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Song et al. Clin Sarcoma Res (2018) 8:16 Page 2 of 8 sarcoma center in the same week. In addition to IHC, we 12 × 4 cm. On cut surface the tumor was pale and fibrous. decided to apply classic cytogenetics and next generation There was extension to surrounding soft tissue (Fig. 3b). sequencing (NGS), which proved to be very helpful in Tumor histology strongly resembled the desmoplastic discriminating these two morphologic mimickers. fibroma diagnosed in case 1, however, with some differ - ences. As shown in Fig.  4a, this tumor also consisted of bundles of moderate cellular tissue, with fibroblast-like, Case presentation spindle cells in abundant collagenous stroma. However, Case 1: a 10-year-old girl, with a history of distal radius there was evidence of invasive growth in trabecular bone fracture 3 years earlier, presented with a firm, nontender and surrounding skeletal muscle tissue. Although nuclear swelling in the same right distal forearm. Her wrist func- chromatin was bland, few normal mitoses were found. tion was unimpaired. As shown in Fig.  1, X-ray exami- Osteoid or trabecular bone was absent. nation revealed a large lobulated, compartmentalized, As depicted in Fig.  4b, cytogenetic analysis showed osteolytic, expansive tumor mass in the metadiaphy- an abnormal karyotype: 47~49,XX,del(13) (q12q32),+ sis of the distal radius. On MRI, the tumor measured 1~2r,+1~2mar,1dmin [cp17]/46,XX [2]. This encom - 35 × 46 × 47  mm and had a well-defined boundary, but passes an interstitial deletion of the long arm of chro- no sclerotic margin. Starting from the distal radius, mosome 13 (q12q32), consistent with heterozygous there was cortical destruction, an extensive soft tissue loss of the RB1 tumor suppressor gene. With cancer component, and impression and bowing of the distal hotspot NGS analysis we found amplification of CDK4 ulna. There were no imaging signs of invasive growth, (NM_000075.3) and an imbalance of the RB1 gene on necrosis or fluid-liquid mirrors. Bone scintigraphy did chromosome 13. not show increased uptake at the location of the lesion. With IHC, tumor cells exhibited strong nuclear stain- These imaging features were consistent with a destructive ing for CDK4 (Fig. 4c) and moderate nuclear staining for tumor that originated from the distal radius, grew slowly, SATB2. RB1 expression was heterogeneous, not com- and then broke through the cortex of the radius into pletely lost. the adjacent soft tissue. The tumor was excised intral - In this case a conclusive diagnosis of DF-LGOS could esionally. Grossly, the largest tumor fragment measured be made, based on histologic features (an invasive fibro - 6 × 5 × 3  cm. On cut surface the tumor tissue was pale blastic tumor with mitotic activity), karyotyping (het- and fibrous. erozygous loss of RB1) and molecular genetics/IHC Tumor histology was reminiscent of desmoid fibroma - (CDK4 amplification). tosis and consistent with desmoplastic fibroma, as it showed a lesion composed of bundles of moderately cel- lular, collagenous tumor tissue with fibroblastic spindle Discussion and conclusions cells with oval, monomorphic nuclei with bland, finely We have presented the clinical presentation, imaging granular chromatin, small nucleoli and ample cytoplasm. studies, gross and microscopic pathology, IHC, cytoge- Mitoses were not found (Fig. 2a). netics and molecular genetics (cancer hotspot analysis) Cytogenetic analysis revealed a normal female kar- of DF and DF-LCOS, two very rare bone tumors, which yotype in 18 cells, with trisomy 8 detected in 2 cells closely resemble each other. (Fig. 2b). DF is very rare indeed. Among 4692 benign bone The cancer hotspot NGS analysis revealed a CTNNB1 tumors treated in the Birmingham Royal Orthopedic hotspot class 5 pathogenic variant in exon 3: p.Ser45Phe Hospital, Evans et  al. [1] identified 13 cases of DF, an and, using IHC, the fibroblastic tumor cells showed more incidence of 0.003%. Böhm et  al. [2] reviewed 189 cases than focal nuclear staining for beta-catenin (Fig.  2c), in of DF reported in the literature up to 1996 and observed support of a diagnosis of desmoplastic fibroma. that, although DF occurs at all ages, children and young Case 2: a 24-year-old woman presented with pro- adults are most commonly affected, three-quarter of gressive pain in the right hip region that had existed patients being younger than 31 years. Sex distribution is for 1  year. X-ray images showed an osteolytic tumor in almost equal. DF most commonly presents in the man- the metadiaphysis of the right distal femur with corti- dible (22%), but also in pelvic bones (13%), and long cal bone destruction on the dorsolateral side. The cen - bones—femur (15%), radius (12%), and tibia (9%). Nota- tral part of the tumor had no matrix calcification. On bly, pathologic fracture of a long bone was reported in MRI, the tumor destroyed the cortex and extended to 12% of patients. Thus, the clinical presentation of our the surrounding soft tissues. There was strong tumor DF case as a tumor in the distal radius of a 10-year-old enhancement after administration of intravenous gado- girl, who had experienced a radius fracture 3 years earlier, linium (Fig.  3a). A resection of the right distal femur matches data from the literature. was performed. The tumor in the distal femur measured Song et al. Clin Sarcoma Res (2018) 8:16 Page 3 of 8 Fig. 1 Conventional AP and lateral radiographs (top left and top middle) show an expansive bubbly lytic bone lesion in the diaphysis‑metaphysis of the right distal radius with a narrow zone of transition, nonsclerotic margins, cortical thinning and destruction, and an accompanying large soft‑tissue mass which appears to compress the distal ulna with bowing of the latter. Bone scintigraphy (top right) shows no increased uptake at the location of the lesion. MRI with coronal T1‑ weighted (bottom left) and gadolinium‑ enhanced T1‑ weighted (bottom middle) images, and axial T2‑ weighted and gadolinium‑ enhanced fat‑suppressed T1‑ weighted images (bottom right) are in keeping with the conventional radiographic findings, and also demonstrate no signs of invasion in surrounding muscles or ulna. Remarkably, in the center of the lesion there is low signal on all sequences (arrows), most strikingly on the T2‑ weighted sequence. Because the combined imaging features suggest a slow‑ growing (most likely benign) process with fibrotic components, the differential diagnostic considerations include desmoplastic fibroma, and (less likely) giant ‑ cell tumor or fibrous dysplasia Song et al. Clin Sarcoma Res (2018) 8:16 Page 4 of 8 Fig. 2 Histology, karyotype and beta‑ catenin nuclear expression in DF. a Histology showing a fibroblastic tumor with little or no nuclear atypia or mitotic activity (H&E, original magnification × 200). As such, the histology of DF resembles that DF‑LGCOS shown in Fig. 4a. b DF karyotype: 47,XX,+8[2]/46,XX[18]. c IHC expression of beta‑ catenin in several tumor cell nuclei of DF (original magnification × 400) It is well appreciated that DF has a high recurrence rate Moreover, infiltrative tumor growth may be seen by after intralesional excision [1, 2], but since DF is a benign microscopy. Mitoses are only rarely found, an important tumor that does not metastasize, we choose to remove criterion to discriminate DF from DF-LCOS or low-grade the radius tumor of this young girl intralesionally, in fibrosarcoma [4]. order to preserve arm and wrist function. Unfortunately, Cytogenetic analysis of our DF case revealed a normal a recurrence has occurred 12 months after surgery. female karyotype in 18 cells, with a trisomy 8 detected As our case illustrates, DF may present as a slowly pro- in 2 cells. To our knowledge, only two papers have been gressive but locally aggressive tumor. As reviewed by published on the cytogenetics and molecular genetics of Nedopil et  al. [3] by imaging studies, DF can show cor- DF. Bridge et  al. [5] found trisomies 8 and 20 in a single tical breakthrough and extension in surrounding soft case of DF, but again, these cytogenetic abnormalities tissue. were also detected in other fibro-osseous bone tumors, Song et al. Clin Sarcoma Res (2018) 8:16 Page 5 of 8 Fig. 3 Conventional AP, lateral radiographs and gross morphology of DF‑LGCOS. a Conventional AP, lateral radiographs (top left and top middle) show an expansive osteolytic lesion in the diaphysis‑metaphysis of the right distal femur with an ill‑ defined border and cortical destruction. Bone scintigraphy (top right) demonstrates increased uptake at the location of the lesion, but no suspicious uptake elsewhere. MRI with sagittal T1‑ weighted (bottom left) and fat‑suppressed proton density‑ weighted (bottom middle) images, and axial T1‑ weighted and gadolinium‑ enhanced fat‑suppressed T1‑ weighted images (bottom right) show the T1 hypointense, T2 hyperintense, and vividly enhancing lesion in the right distal femur as a large soft‑tissue mass with cortical breakthrough and extra‑ osseous expansion. The combined imaging features are highly suggestive of an aggressive malignant lesion, with osteosarcoma, Ewing sarcoma, and chondrosarcoma being the main differential diagnostic considerations. b Gross specimen of DF‑LGCOS, showing a white, fibrous tumor of the distal femur with cortical breakthrough and invasion of soft tissue. As such, the gross appearance of DF‑LGCOS resembles DF by which these are noncontributory to a certain DF tumors [9] or fibrous soft tissue tumors [12]. Moreover, diagnosis. IHC for beta-catenin is not specific for APC/CTNNB1 An abnormal karyotype 46,XX,del(11)(q13q23),der(19) mutations in fibro-osseous bone tumors. CTNNB1 muta - t(11;19)(q13;p13)del(11)(q23) was reported by Trombetta tions are a rare molecular event in the few cases of DF et al. [6] in a DF occurring in the femur of a 20-year-old that have been analyzed [7–9]. In fact, Flucke et  al. [8] female patient. It was hypothesized that loss of a genomic found a p.T41A CTNNB1 mutation in 1 out of 2 cases of region in 11q, an area containing the genes RBM14, DF arising in the mandible, Horvai and Jordan [9] found RBM4, RBM4B, SPTBN2, and C11orf80 may be of patho- an APC mutation, but no CTNNB1 mutation in a single genic significance. DF analyzed, and Hauben et  al. [7] found no CTNNB1 Using IHC, others and we have noticed nuclear stain- mutation in six DF cases. Using NGS, we detected a ing of beta-catenin in DF [3, 4, 7–11]. However, although CTNNB1 hotspot class 5 pathogenic variant in exon 3: nuclear expression of beta-catenin supports a diagnosis p.S45F, which is a gain of function mutation. Clearly, to of DF, one has to be aware that nuclear immunostaining be able to estimate the real frequency of CTNNB1 muta- of beta-catenin also occurs in other fibro-osseous bone tions in DF, more cases have to be studied, preferably Song et al. Clin Sarcoma Res (2018) 8:16 Page 6 of 8 Fig. 4 Histology, karyotype and CDK4 expression in DF‑LGOS. a Histology showing a fibroblastic tumor with permeative invasive growth (H&E, original magnification × 100). As such, the histology of DF‑LGCOS resembles that of DF, shown in Fig. 2a. b DF‑LGOS karyotype: 47~49,XX,del(13) (q12q32),+1~2r,+1~2mar,1dmin[cp17]/46,XX[2]. c Diffuse nuclear expression of CDK4 in cell nuclei of DF‑LGCOS (original magnification × 200) using NGS, since NGS has a higher sensitivity compared tumor that had invaded bone. However, given the imag- with traditional DNA sequencing methods in picking up ing features, in particular the bubbly compartmental- CTNNB1 mutations [13] Interestingly, the S45F CTNNB ized appearance of the radius tumor and the bowing of mutation also occurs in desmoid fibromatosis, in particu - the distal ulna without bone invasion (see Fig.  1), we lar in aggressive and recurrent lesions [14]. However, it regarded the radius tumor in this girl as a slow growing remains to be proven that DF is the bony counterpart of primary bone tumor with soft tissue extension, a clinical desmoid fibromatosis of soft tissue. In this respect, one presentation consistent with a histopathologic diagnosis may argue whether our case 1 represents a soft tissue of desmoplastic fibroma of bone. Song et al. Clin Sarcoma Res (2018) 8:16 Page 7 of 8 The majority of central osteosarcomas are high- DF. Both are fibrous tumors of bone with are slowly grade conventional osteosarcomas, in which the tumor progressive and locally aggressive showing cortical cells show severe nuclear atypia and produce a variable breakthrough. DF and DF-LGCOS consist of bundles of amount of cartilaginous or osteoid matrix. High grade moderately cellular collagenous tumor tissue with spin- osteosarcomas with severe nuclear atypia, but little or no dled fibroblast-like cells. The two cases reported herein matrix formation can be confirmed by SATB2 immuno - show that karyotyping and molecular genetic analysis histochemistry [15, 16]. may contribute to a conclusive diagnosis, DF show- Our DF-LGCOS case is part of another subset of low ing CTNNB1 S45F mutation and DF-LGCOS showing grade central osteosarcomas namely the ones that resem- CDK4 amplification. ble DF and have little or no osteoid matrix deposition. So far, this very rare OS subtype has only been described in Abbreviations case reports and small series [17, 18]. Most likely these DF: desmoplastic fibroma; DF‑like LGCOS: low‑ grade central osteosarcoma rare DF-LCOS have been included in the histological (LGCOS) resembling desmoplastic fibroma; NGS: next generation sequencing; IHC: immunohistochemistry; LGCOS: low‑ grade central osteosarcoma; CC1: spectrum of fibrosarcomas of bone [4]. We agree with cell conditioning buffer 1. Horvai and Jordan [9], who stated that it seems logical that at least a subset of fibrosarcomas of bone are actu - Authors’ contributions WS observed pathology specimens, participated in the study design and ally osteosarcomas with little or no osteoid or bone for- drafted the manuscript. EB and AMCJ performed classic cytogenetics and next mation. Surprisingly, in the 2013 WHO classification of generation sequencing, respectively. TCK interpreted imaging features. PCJ tumors of soft tissue and bone, fibrosarcomas of bone are performed the surgery, managed the patient and completed the clinical data collection. JVMGB conceived of the study, participated in its design. AJS con‑ defined as intermediate to high grade spindle cell tumors ceived, designed and supervised this article. All authors read and approved that lack any line of differentiation other than fibroblas - the final manuscript. tic, leaving little room for the recognition of low grade Author details variants, also excluding DF- LGCOS. Department of Pathology and Medical Biology, University Medical Center Strong and diffuse SATB2 nuclear IHC staining reflects Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The an osteoblastic line of differentiation. To date, only one Netherlands. Department of Genetics, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Nether‑ Chinese study investigated SATB2 expression in low lands. Department of Radiology, Nuclear Medicine and Molecular Imaging, grade osteosarcoma and desmoplastic fibroma. These University Medical Center Groningen, University of Groningen, P.O. Box 30.001, authors found that low-grade osteosarcoma and fibrous 9700 RB Groningen, The Netherlands. Department of Orthopedic Surgery, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, dysplasia are positive for SATB2, while desmoplas- 9700 RB Groningen, The Netherlands. Department of Pathology, Leiden tic fibroma, low-grade fibrosarcoma and other fibrous University Medical Center, Leiden, The Netherlands. tumors are negative [19]. Acknowledgements The notion that DF-LGCOS is an osteosarcoma vari - We want to acknowledge Tom van Wezel and Dina Ruano Neto (Pathology, ant is also supported by the cytogenetics and molecular LUMC) for setting up the NGS pipeline. genetics of our second case. DF-LGCOS had a karyotype Competing interests with interstitial deletion of the long arm of chromosome The authors declare that they have no competing interests. 13 (q12q32), consistent with loss of the RB1 tumor sup- pressor gene, a genetic abnormality found in a substantial Availability of data and materials The dataset supporting the conclusions of this article is included within the number of osteosarcomas. Notably, cancer hotspot NGS article. analysis revealed amplification of CDK4 and IHC showed overexpression of CDK4. Consent for publication Written informed consent for publication of their clinical details and/or clinical The prototypical LGCOS (which resembles parosteal images was obtained from the patient. A copy of the consent form is available osteosarcoma) usually produces abundant bone matrix for review by the Editor of this journal. and contains trabecular woven bone. The fibroblas - Ethics approval and consent to participate tic stromal cells of the prototypical LGCOS show slight All procedures performed in studies involving human participants were in nuclear atypia and mitosis are not easily discerned. This accordance with the ethical standards of the institutional and/or national subset of LGCOS often has gain or amplification of the research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study met the criteria of MDM2 and/or CDK4 genes, which can be visualized by the code of conduct for responsible use of human tissue that is used in the their nuclear expression by IHC [19]. By IHC, CDK4 is Netherlands (Dutch federation of biomedical scientific societies; http://www. positive in the majority of LGOS, and, when combined feder a.org). with MDM2 immunostaining, the sensitivity and speci- Funding ficity for LGOS is 100% and 97.5%, respectively [20]. Wangzhao Song receives funding from the China Scholarship Council (CSC) The clinical presentation, imaging studies and gross program (Grant No: 201606940023). morphology of DF-LGCOS shows much overlap with Song et al. Clin Sarcoma Res (2018) 8:16 Page 8 of 8 10. Woods TR, Cohen DM, Islam MN, et al. Desmoplastic fibroma of the man‑ Publisher’s Note dible: a series of three cases and review of literature. Head Neck Pathol. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 2015;9:196–204. lished maps and institutional affiliations. 11. Okubo T, Saito T, Takagi T, et al. Desmoplastic fibroma of the rib with cystic change: a case report and literature review. Skeletal Radiol. Received: 18 May 2018 Accepted: 23 July 2018 2014;43:703–8. 12. Carlson JW, Fletcher CD. Immunohistochemistry for beta‑ catenin in the differential diagnosis of spindle cell lesions: analysis of a series and review of the literature. Histopathology. 2007;51:509–14. 13. Colombo C, Urbini M, Astolfi A, et al. Novel intra‑ genic large deletions References of CTNNB1 gene identified in WT desmoid‑type fibromatosis. Genes 1. Evans S, Ramasamy A, Jeys L, et al. Desmoplastic fibroma of bone: a rare Chromosomes Cancer. 2018. https ://doi.org/10.1002/gcc.22644 . bone tumour. J Bone Oncol. 2014;3:77–9. 14. van Broekhoven DL, Verhoef C, Grünhagen D, et al. Prognostic value of 2. Bohm P, Krober S, Greschniok A, et al. Desmoplastic fibroma of the bone. CTNNB1 gene mutation in primary sporadic aggressive fibromatosis. Ann A report of two patients, review of the literature, and therapeutic implica‑ Surg Oncol. 2015;22:1464–70. tions. Cancer. 1996;78:1011–23. 15. Conner JR, Hornick JL. SATB2 is a novel marker of osteoblastic differentia‑ 3. Nedopil A, Raab P, Rudert M. Desmoplastic fibroma: a case report with tion in bone and soft tissue tumours. Histopathology. 2013;63:36–49. three years of clinical and radiological observation and review of the 16. Davis JL, Horvai AE. Special AT‑rich sequence ‑binding protein 2 (SATB2) literature. Open Orthop J. 2013;8:40–6. expression is sensitive but may not be specific for osteosarcoma as com‑ 4. Saito T, Oda Y, Tanaka K, et al. Low‑ grade fibrosarcoma of the proximal pared with other high‑ grade primary bone sarcomas. Histopathology. humerus. Pathol Int. 2003;53:115–20. 2016;69:84–90. 5. Bridge JA, Swarts SJ, Buresh C, et al. Trisomies 8 and 20 characterize a 17. Kurt AM, Unni KK, McLeod RA, et al. Low‑ grade intraosseous osteosar‑ subgroup of benign fibrous lesions arising in both soft tissue and bone. coma. Cancer. 1990;65:1418–28. Am J Pathol. 1999;154:729–33. 18. Bertoni F, Bacchini P, Fabbri N, et al. Osteosarcoma. Low‑ grade 6. Trombetta D, Macchia G, Mandahl N, et al. Molecular genetic charac‑ intraosseous‑type osteosarcoma, histologically resembling parosteal terization of the 11q13 breakpoint in a desmoplastic fibroma of bone. osteosarcoma, fibrous dysplasia, and desmoplastic fibroma. Cancer. Cancer Genet. 2012;205:410–3. 1993;71:338–45. 7. Hauben E, Jundt G, Cleton‑ Jansen AM, et al. Desmoplastic fibroma of 19. Chen CY, Zhang HZ, Jiang ZM, et al. Value of MDM2, CDK4 and SATB2 bone: an immunohistochemical study including beta‑ catenin expression immunohistochemistry in histologic diagnosis of low‑ grade osteosar‑ and mutational analysis for beta‑ catenin. Hum Pathol. 2005;36:1025–30. coma. Zhonghua Bing Li Xue Za Zhi. 2016;45:387–92. 8. Flucke U, Tops BB, van Diest PJ, et al. Desmoid‑type fibromatosis of the 20. Yoshida A, Ushiku T, Motoi T, et al. Immunohistochemical analysis of head and neck region in the paediatric population: a clinicopathological MDM2 and CDK4 distinguishes low‑ grade osteosarcoma from benign and genetic study of seven cases. Histopathology. 2014;64:769–76. mimics. Mod Pathol. 2010;23:1279–88. 9. Horvai A, Jordan R. Fibro‑ osseous lesions of the craniofacial bones: β‑ catenin immunohistochemical analysis and CTNNB1 and APC mutation analysis. Head Neck Pathol. 2014;8(3):291–7. Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions

Journal

Clinical Sarcoma ResearchSpringer Journals

Published: Aug 23, 2018

There are no references for this article.