|Year : 2019 | Volume
| Issue : 4 | Page : 947-952
Undifferentiated sarcoma of the soft tissues with cystic degeneration: Case report and review of literature
Changhua Wu1, Liang Wang1, Lei Guo1, Lihong Zhang2, Jing Li1
1 Department of Intervention and Hemangioma, Qilu Children's Hospital of Shandong University, Jinan City, Shandong Province, China
2 Department of Pathology, Qilu Children's Hospital of Shandong University, Jinan City, Shandong Province, China
|Date of Web Publication||14-Aug-2019|
Department of Intervention and Hemangioma, Qilu Children's Hospital of Shandong University, Room 23976, Jingshi Road, Jinan City, Shandong Province 250022
Source of Support: None, Conflict of Interest: None
Undifferentiated sarcoma (UNDS) of the soft tissue is an exceedingly rare disease. Its diagnosis depends mainly on molecular and immunohistochemical analyses to exclude other soft-tissue sarcomas. It is difficult to confirm a positive diagnosis by imaging pathological features because of their rarity and similarity with other conditions. Since 2013, only 13 cases of undifferentiated soft-tissue sarcoma, mostly diagnosed through imaging of solid tumors in infant and children, have been reported. The authors present a rare case of a 3-month-old Chinese boy with UNDS primarily in the left lower extremity and characterized by a cystic and solid growth pattern.
Keywords: Soft tissue sarcoma, undifferentiated sarcoma, UNDS
|How to cite this article:|
Wu C, Wang L, Guo L, Zhang L, Li J. Undifferentiated sarcoma of the soft tissues with cystic degeneration: Case report and review of literature. J Can Res Ther 2019;15:947-52
|How to cite this URL:|
Wu C, Wang L, Guo L, Zhang L, Li J. Undifferentiated sarcoma of the soft tissues with cystic degeneration: Case report and review of literature. J Can Res Ther [serial online] 2019 [cited 2019 Aug 17];15:947-52. Available from: http://www.cancerjournal.net/text.asp?2019/15/4/947/264306
| > Introduction|| |
Undifferentiated sarcoma (UNDS) is a rare malignant soft-tissue tumor. UNDS is common among infants and children aged between 0 and 20 years., The typical clinical manifestations of this disease are painless masses on the extremities, back, flank, abdominal wall, or on the head and neck., However, confirming a positive diagnosis by imaging is difficult despite the analysis of pathological features because of the rarity of the disease and morphologic similarities with other conditions. Furthermore, it is difficult to distinguish UNDS from other tumors with similar clinicopathological characteristics using limited technology; this may lead to a relatively large number of UNDS cases being reported. The application of new technologies for molecular and immunohistochemical analyses have enabled the exclusion of rhabdomyosarcoma, Ewing sarcoma (ES), synovial sarcoma, and high-grade pleomorphic UNDS while diagnosing UNDS. Thus, the current number of actual UNDS patients is obviously lesser than that in the past,,, according to a new definition in 2013. Only 13 cases of undifferentiated soft-tissue sarcoma (USTS), mostly including imaging manifestations of solid tumors in infant and children groups, have been reported. The authors present a rare case of a 3-month-old Chinese boy with UNDS primarily within the lower left extremity and characterized by a cystic and solid growth pattern.
| > Case Report|| |
A 3-month-old boy was brought to our outpatient department by his father with a complaint of progressive swelling in the left lower extremity [Figure 1]a, which was discovered at birth. Prenatal screening and family histories were unremarkable. Physical examination revealed a vague margin and soft and nontender swelling in the left thigh. Skin of the tumor surface was light purple with nonulceration. Blood tests, including tumor marker examination, showed normal results.
|Figure 1: (a) Mass located in the left lower extremity; (b and c) ultrasound images showing a dark, opaque, reticulate area containing fluid (b) measuring 8.1 cm × 6.0 cm × 4.8 cm with a few blood vessels (c) passing through, surrounded by the thickened, density-reinforced soft tissue. (d-f) The MRI revealed a massive tumor, with long T1 and short T2 signal intensities, and multiple cystic lesions separated by fats. Postcontrast inhomogeneous enhancement was seen within the mass, while no enhancement was seen within the cystic lesions. (g) Surgical resection of the tumor|
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All imaging examinations suggesting vascular anomalies included color Doppler ultrasound and magnetic resonance imaging (MRI). The color Doppler images showed a reticulate opaque dark area of fluid [Figure 1]b measuring 8.1 cm × 6.0 cm × 4.8 cm with a few blood vessels [Figure 1]c passing through, surrounded by thickened, density-reinforced soft tissue. The size of tumor was 11.6 cm × 6.1 cm × 3.7 cm, as measured by the color Doppler ultrasound. The contrast-enhanced MRI also revealed a massive tumor, with long T1 and short T2 signal intensities, and multiple cystic lesions separated by fats [Figure 1]d and [Figure 1]e. Postcontrast inhomogeneous enhancement was seen within the mass, while no enhancement was seen within the cystic lesions [Figure 1]f; the biopsy revealed undifferentiated carcinoma. The child underwent surgical treatment after the contraindications of surgery were eliminated; a cystic and solid aggressive lesion 18 cm × 13 cm × 10 cm in size, grossly adhering to the subcutaneous tissue and muscle, was seen [Figure 1]g. Histopathological examination revealed malignant nuclear features with cellular polymorphism [Figure 2]a and [Figure 2]b. In addition, Vimentin positivity and weak Ki-67 positivity were seen, consistent with the diagnosis of high-grade, undifferentiated (embryonal) sarcoma [Figure 2]c, [Figure 2]d, [Figure 2]e. Immunohistochemistry (IHC) did not show Myogenin and MyoD1 positivity, making rhabdomyosarcoma unlikely. In addition, the tumor cells were negative for CD33, SMA, Desmin, S-100, CD34, CD99, and CK. He was administered VAC chemotherapy with vincristine (0.05 mg/kg for day 1), actinomycin D (0.045 mg/kg for day 1), and cyclophosphamide (40 mg/kg for day 1) after surgical treatment. Repeated systemic imaging revealed no evidence of local tumor recurrence or distant metastasis during multicycle chemotherapy.
|Figure 2: Pathology of UNDS: (a and b) Hematoxylin and eosin-stained sections an intermediate (×400). (c-e) Representative high-magnification images (×400) of immunohistochemical staining for Vimentin+ (c), CD99− (d), and Ki67+/− (e)|
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| > Discussion|| |
UNDS is defined as a highly malignant mesenchymal neoplasm evolved from malignant fibrous histiocytoma; it lacks specific diagnostic morphological features. These tumors were originally designated as “small round-cell sarcoma, type indeterminate,” incorporating all sarcomas without identifying a specific lineage. In 2013, the World Health Organization reviewed the classification of soft-tissue tumors and established the classification and nomenclature of UNDS, further subclassifying them into the spindle-cell, round-cell, epithelioid, and pleomorphic subsets; however, individual morphologic patterns often coexist., Previous literatures have reported 13 cases of USTS in infant and children groups after 2013, with a relatively complete description of clinicopathologic features [Table 1].,,,,,,, In these 13 cases, the mean age at the time of diagnosis was 8.68 years (range: 8 days–18 years).
|Table 1: Clinicopathologic features of 1 tumor in this current series and 12 previously reported tumors|
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The major complaint in newly diagnosed patients is a rapidly growing lesion on the body surface. The group of UNDS emphasized their primitive mesenchymal nature became smaller and more refined profited from the new diagnostic adjuncts such as IHC, cytogenetics, and molecular genetics. Fortunately, the presence of certain morphological and immunohistochemical features raised the possibility of a specific sarcoma subtype in individual cases, for example, S100 positivity occurs with malignant peripheral nerve sheath tumor (MPNST) and PEComa, and CD99 positivity occurs with Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET); however, these are not perfectly equivalent. In a recent study of infantile UNDS, IHC showed Vimentin (92%) CD117 (92%) and vascular endothelial growth factor (69%) positivity; 8%–23% of the cells showed focal positivity for epithelial, neural, or myogenic markers. However, research has shown that virtually all the neoplastic cells were Vimentin positive and showed positive nuclear staining with INI-1 antibodies; approximately 5% of the cells showed membranous CD99 immunoreactivity. In our case, Vimentin positivity was also shown, but with poor specificity. In addition, the immunohistochemical characteristics of UNDS s associated with CIC-DUX4 and BCOR-CCNB3 fusion genes, showing not only a small round-cell component but also a myxoid/epithelioid component with low mitotic activity, were reported by Yamada et al.
A thorough morphological and molecular genetic analysis of pediatric soft-tissue sarcoma is necessary to reveal features such as a sheet-like proliferation of densely packed, round-, or spindled-shaped tumor cells. In children, UNDS is mostly characterized by round- or spindle-shaped cells and shows a morphologic overlap with a variant of ES, once called atypical ES.
Molecular genetic analysis was useful for the differentiation of UNDS from some other soft-tissue sarcomas, such as synovial sarcoma (SYT/SSX fusion transcript positive), ES/PNET (EWS gene rearrangement, CD99 positive), and infantile fibrosarcoma (ETV6/NTRK3 fusion transcript positive). In fact, up to 60% of tumors expressed some form of so-called lineage-specific antigens. BCOR-CCNB3 fusions have been frequently reported in UNDS;, individual cases of undifferentiated small round-cell sarcomas with CIC-DUX4 fusion have also been reported.,, For the pediatric population, the BCOR-CCNB3 fusion gene mostly resulted from the paracentric inversion of the X chromosome. Using whole transcriptome paired-end RNA sequencing, Peters et al. unexpectedly identified BCOR-CCNB3 fusion transcripts in undifferentiated spindle-cell sarcoma. In particular, gene profiling experiments indicated that BCOR-CCNB3-positive cases are biologically distinct from other sarcomas, particularly ES.
Through a systematic comparison between ES and ES-like cases at the molecular and immunohistochemical levels, individual cases of these UNDS were first recognized to have the characteristic karyotypic translocation. Subsequently, the results of a study on 22 patients suggest the possibility of a newly defined subgroup of primitive round-cell sarcomas characterized by CIC rearrangements. In 2017, a case of pediatric UNDS with a novel variant of t (4;19) CIC-DUX4 fusion transcript was reported. Tsukamoto et al. reported a case of t(10;19) CIC-DUX4 undifferentiated small round-cell sarcoma. As indicated, in addition to CIC-DUX4 fusions, CIC-FOXO4 fusions have also been described in tumors occurring in peripheral soft tissues.
Nevertheless, it is still very difficult to make a definite diagnosis through preoperative imaging without characteristic manifestations. Ultrasonic imaging has been rarely described by UNDS scholars; the ultrasonic parameters in our case are similar to those of undifferentiated embryonal sarcoma of the liver. The color Doppler ultrasound images demonstrate a round hyperechoic lesion within several anechoic spaces, which correspond to fluid-filled spaces. These images represent a diagnostic challenge for sonographers in distinguishing UNDS from lymphatic malformations. In addition, color Doppler flow imaging revealed lots of spots and slices style color blood-flow signals which represent the arteries originating from the superficial femoral artery and supplying blood to the neoplasm. MRI, which is better than computed tomography, has a higher soft-tissue contrast and is the common diagnostic method for soft-tissue sarcoma. Although MRI revealed vascular anomalies, it was responsible for the wrong initial diagnosis in our case. It showed a mass with predominantly inhomogeneous hypointense signals compared to those of the normal surrounding tissue and a lack of marked enhancement of cystic lesions. The tail sign was a common MRI feature of UNDS and was also associated with worse local recurrence-free survival (P = 0.019). According to a study on 35 UNDS patients, the incidence of this feature was nearly 50%. This may contribute to preoperative diagnosis, illness evaluation, and therapeutic effect prediction. Furthermore, the addition of functional MR procedures to a routine MR protocol, Dynamic contrast-enhanced MRI (DCE-MRI) in particular, offers a specificity of >95% for distinguishing recurrent sarcoma from postsurgical scarring.
Clinically, a novel finding of this study was that patients with USTS can achieve long-term survival with multimodal therapy including chemotherapy and surgery. Somers et al. described the cases of 13 children under 16 years of age who were treated for UNDS of the trunk and extremities, of which four received only chemotherapy, one received chemotherapy following radiotherapy, four underwent operation with chemotherapy, and three received a combination of all three; the data for one patient were lost. The 5-year event-free and overall survival rates were 54% and 74%, respectively. The prognosis of UNDS was closely related to tumor invasiveness and size, age at diagnosis, primary tumor site, resection margins, initial resectability, and response to radiotherapy and chemotherapy. Somers et al. have suspected that severe atypia was associated with decreased survival (P = 0.048).
In summary, due to the tremendous development of IHC and molecular biology techniques, the understanding of soft-tissue sarcoma continues to deepen. However, because UNDS is a highly heterogeneous tumor, its diagnosis is based on exclusion. With regard to the diagnosis and treatment of UNDS, we strongly recommend caution, especially during the imaging of cystic solid tumors. Needle biopsy is a wise choice to confirm the initial diagnosis. The presence of certain common morphological and immunohistochemical features in the absence of specific genetic abnormalities allows for the correct diagnosis of pediatric USTS.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Pawel BR, Hamoudi AB, Asmar L, Newton WA Jr., Ruymann FB, Qualman SJ, et al.
Undifferentiated sarcomas of children: Pathology and clinical behavior – an intergroup rhabdomyosarcoma study. Med Pediatr Oncol 1997;29:170-80.
Alaggio R, Bisogno G, Rosato A, Ninfo V, Coffin CM. Undifferentiated sarcoma: Does it exist? A clinicopathologic study of 7 pediatric cases and review of literature. Hum Pathol 2009;40:1600-10.
Sebire NJ, Ramsay AD, Levitt G, Malone M, Risdon RA. Aberrant immunohistochemical expression in nonrhabdomyosarcoma soft tissue sarcomas of infancy: Retrospective review of clinical material. Pediatr Dev Pathol 2002;5:579-86.
Somers GR, Gupta AA, Doria AS, Ho M, Pereira C, Shago M, et al.
Pediatric undifferentiated sarcoma of the soft tissues: A clinicopathologic study. Pediatr Dev Pathol 2006;9:132-42.
Randall RL, Albritton KH, Ferney BJ, Layfield L. Malignant fibrous histiocytoma of soft tissue: An abandoned diagnosis. Am J Orthop (Belle Mead NJ) 2004;33:602-8.
Newton WA Jr., Gehan EA, Webber BL, Marsden HB, van Unnik AJ, Hamoudi AB, et al.
Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and proposal for a new classification – An intergroup rhabdomyosarcoma study. Cancer 1995;76:1073-85.
Fletcher CD. The evolving classification of soft tissue tumours – An update based on the new 2013 WHO classification. Histopathology 2014;64:2-11.
Jo VY, Doyle LA. Refinements in sarcoma classification in the current 2013 World Health Organization classification of tumours of soft tissue and bone. Surg Oncol Clin N
van Bommel A, Aslam R, Brundler MA, Hobin D, Jester A. Early tendon transfer after wide resection of an undifferentiated sarcoma of the forearm in a neonate: A case report. J Plast Reconstr Aesthet Surg 2013;66:1287-90.
Martín Vañó S, Berbegall AP, Blanquer NL, Garrido-Colino C. Female new-born with undifferentiated sarcoma defined by BCOR-CCNB3 fusion transcript. J Clin Exp Pathol 2015;5:244.
Varma K, Gupta P, Das P, Singh P, Misra V. CD10 positive recurrent undifferentiated mammary sarcoma in a young female: A rare case report with brief review of literature. Rare Tumors 2015;7:5737.
Adesina OO, Zaugg BE, Dries DC, Palmer CA, Patel BC. Undifferentiated nonrhabdomyosarcoma soft tissue sarcoma of the orbit. Ophthalmic Plast Reconstr Surg 2017;33:e57-60.
Donahue JE, Yakirevich E, Zhong S, Treaba DO, Lakis NS, Ali SM, et al.
Primary spinal epidural CIC-DUX4 undifferentiated sarcoma in a child. Pediatr Dev Pathol 2018;21:411-7.
Hery AL, Ornvold K, Memoli V, Bridge J, Linos K. A case of CIC-rearranged undifferentiated round-cell sarcoma with exclusive spindled morphology and diffuse CD99 positivity: A potential pitfall. Histopathology 2017;70:314-6.
Krskova L, Stejskalova E, Kabickova E, Mrhalova M, Kodet R. A t(4;19) pediatric undifferentiated sarcoma with a novel variant of the CIC-DUX4 fusion transcript. Pathol Res Pract 2017;213:281-5.
Matsuyama A, Shiba E, Umekita Y, Nosaka K, Kamio T, Yanai H, et al.
Clinicopathologic diversity of undifferentiated sarcoma with BCOR-CCNB3 fusion: Analysis of 11 cases with a reappraisal of the utility of immunohistochemistry for BCOR and CCNB3. Am J Surg Pathol 2017;41:1713-21.
Yamada Y, Kuda M, Kohashi K, Yamamoto H, Takemoto J, Ishii T, et al.
Histological and immunohistochemical characteristics of undifferentiated small round cell sarcomas associated with CIC-DUX4 and BCOR-CCNB3 fusion genes. Virchows Arch 2017;470:373-80.
Christopher D. Fletcher M. WHO classification of tumours of soft tissue and bone[M]. IARC Press, 2013. p. 95-104.
Peters TL, Kumar V, Polikepahad S, Lin FY, Sarabia SF, Liang Y, et al.
BCOR-CCNB3 fusions are frequent in undifferentiated sarcomas of male children. Mod Pathol 2015;28:575-86.
Haidar A, Arekapudi S, DeMattia F, Abu-Isa E, Kraut M. High-grade undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: Emerging entities of soft tissue tumors with unique histopathologic features – A case report and literature review. Am J Case Rep 2015;16:87-94.
Sugita S, Arai Y, Tonooka A, Hama N, Totoki Y, Fujii T, et al.
A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: A genetically distinct variant of Ewing-like sarcoma. Am J Surg Pathol 2014;38:1571-6.
Ludwig K, Alaggio R, Zin A, Peron M, Guzzardo V, Benini S, et al.
BCOR-CCNB3 undifferentiated sarcoma-does immunohistochemistry help in the identification? Pediatr Dev Pathol 2017;20:321-9.
Li WS, Liao IC, Wen MC, Lan HH, Yu SC, Huang HY, et al.
BCOR-CCNB3-positive soft tissue sarcoma with round-cell and spindle-cell histology: A series of four cases highlighting the pitfall of mimicking poorly differentiated synovial sarcoma. Histopathology 2016;69:792-801.
Pierron G, Tirode F, Lucchesi C, Reynaud S, Ballet S, Cohen-Gogo S, et al.
A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet 2012;44:461-6.
Specht K, Sung YS, Zhang L, Richter GH, Fletcher CD, Antonescu CR, et al.
Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: Further evidence toward distinct pathologic entities. Genes Chromosomes Cancer 2014;53:622-33.
Italiano A, Sung YS, Zhang L, Singer S, Maki RG, Coindre JM, et al.
High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas. Genes Chromosomes Cancer 2012;51:207-18.
Tsukamoto Y, Futani H, Yoshiya S, Watanabe T, Kihara T, Matsuo S, et al.
Primary undifferentiated small round cell sarcoma of the deep abdominal wall with a novel variant of t(10;19) CIC-DUX4 gene fusion. Pathol Res Pract 2017;213:1315-21.
Gabor F, Franchi-Abella S, Merli L, Adamsbaum C, Pariente D. Imaging features of undifferentiated embryonal sarcoma of the liver: A series of 15 children. Pediatr Radiol 2016;46:1694-704.
Yoo HJ, Hong SH, Kang Y, Choi JY, Moon KC, Kim HS, et al.
MR imaging of myxofibrosarcoma and undifferentiated sarcoma with emphasis on tail sign; diagnostic and prognostic value. Eur Radiol 2014;24:1749-57.
Del Grande F, Subhawong T, Weber K, Aro M, Mugera C, Fayad LM, et al.
Detection of soft-tissue sarcoma recurrence: Added value of functional MR imaging techniques at 3.0 T. Radiology 2014;271:499-511.
Hayes-Jordan A. Recent advances in non-rhabdomyosarcoma soft-tissue sarcomas. Semin Pediatr Surg 2012;21:61-7.
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