Undifferentiated pleomorphic sarcoma (UPS) is an inclusive term used for sarcomas that defy formal sub-classification. The frequency with which this diagnosis is assigned has decreased in the last twenty years. This is because when implemented, careful histologic assessment, immunohistochemistry, and ultra-structural evaluation can often determine lineage of differentiation. Further attrition in the diagnostic frequency of UPS may arise by using array-comparative genomic hybridization. Gene expression arrays are also of potential use as they permit hierarchical gene clustering. Appraisal of the literature is difficult due to a historical perspective in which specific molecular diagnostic methods were previously unavailable. The American Joint Committee on Cancer (AJCC) classification has changed with different inclusion criteria. Taxonomy challenges also exist with the older term “malignant fibrous histiocytoma” being replaced by “UPS”. In 2010 an analysis of multiple sarcoma expression databases using a 170-gene predictor, re-classified most MFH and “not-otherwise-specified” (NOS) tumors as liposarcomas, leiomyosarcomas or fibrosarcomas. Interestingly, some of the classifier genes are potential molecular therapeutic targets including Insulin-like growth factor 1 (IGF-1), Peroxisome proliferator-activated receptor γ (PPARγ), Nerve growth factor β (NGF β) and Fibroblast growth factor receptor (FGFR).
References
[1]
Crozat, A.; Aman, P.; Mandahl, N.; Ron, D. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 1993, 363, 640–644, doi:10.1038/363640a0.
[2]
Clark, J.; Rocques, P.J.; Crew, A.J.; Gill, S.; Shipley, J.; Chan, A.M.; Gusterson, B.A. Cooper CSIdentification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nat. Genet. 1994, 7, 502–508.
[3]
Quesada, J.; Amato, R. The molecular biology of soft-tissue sarcomas and current trends in therapy. Sarcoma 2012, 2012, 849456.
[4]
Dunham, M.A.; Neumann, A.A.; Fasching, C.L.; Reddel, R.R. Telomere maintenance by recombination in human cells. Nat. Genet. 2000, 26, 447–450.
[5]
Ulaner, G.A.; Hoffman, A.R.; Otero, J.; Huang, H.Y.; Zhao, Z.; Mazumdar, M.; Gorlick, R.; Meyers, P.; Healey, J.H.; Ladanyi, M. Divergent patterns of telomere maintenance mechanisms among human sarcomas: Sharply contrasting prevalence of the alternative lengthening of telomeres mechanism in Ewing’s sarcomas and osteosarcomas. Genes Chromosomes Cancer 2004, 41, 155–162, doi:10.1002/gcc.20074.
[6]
Scheel, C.; Schaefer, K.L.; Jauch, A.; Keller, M.; Wai, D.; Brinkschmidt, C.; van Valen, F.; Boecker, W.; Dockhorn-Dworniczak, B.; Poremba, C. Alternative lengthening of telomeres is associated with chromosomal instability in osteosarcomas. Oncogene 2001, 20, 3835–3844.
[7]
Nielsen, T.O.; West, R.B. Translating gene expression into clinical care: Sarcomas as a paradigm. J. Clin. Oncol. 2010, 28, 1796–1805, doi:10.1200/JCO.2009.26.1917.
[8]
Fletcher, C.D. Pleomorphic malignant fibrous histiocytoma: Fact or fiction? A critical reappraisal based on 159 tumors diagnosed as pleomorphic sarcoma. Am. J. Surg. Pathol. 1992, 16, 213–228, doi:10.1097/00000478-199203000-00001.
[9]
Fletcher, C.D.; Gustafson, P.; Rydholm, A.; Willén, H.; Akerman, M. Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas: Prognostic relevance of subclassification. J. Clin. Oncol. 2001, 19, 3045–3050.
[10]
Mentzel, T.; Calonje, E.; Wadden, C.; Camplejohn, R.S.; Beham, A.; Smith, M.A.; Fletcher, C.D. Myxofibrosarcoma. Clinicopathologic analysis of 75 cases with emphasis on the low-grade variant. Am. J. Surg. Pathol. 1996, 20, 391–405.
[11]
McCormick, D.; Mentzel, T.; Beham, A.; Fletcher, C.D. Dedifferentiated liposarcoma. Clinicopathologic analysis of 32 cases suggesting a better prognostic subgroup among pleomorphic sarcomas. Am. J. Surg. Pathol. 1994, 18, 1213–1223, doi:10.1097/00000478-199412000-00004.
[12]
Henricks, W.H.; Chu, Y.C.; Goldblum, J.R.; Weiss, S.W. Dedifferentiated liposarcoma: A clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am. J. Surg. Pathol. 1997, 21, 271–281, doi:10.1097/00000478-199703000-00002.
[13]
Merck, C.; Angervall, L.; Kindblom, L.G.; Odén, A. Myxofibrosarcoma. A malignant soft tissue tumor of fibroblastic-histiocytic origin. A clinicopathologic and prognostic study of 110 cases using multivariate analysis. Acta Pathol. Microbiol. Immunol. Scand. Suppl. 1983, 282, 1–40.
[14]
Nielsen, T.O.; West, R.B.; Linn, S.C.; Alter, O.; Knowling, M.A.; O’Connell, J.X.; Zhu, S.; Fero, M.; Sherlock, G.; Pollack, J.R.; et al. Molecular characterisation of soft tissue tumours: A gene expression study. Lancet 2002, 359, 1301–1307.
[15]
Nakayama, R.; Nemoto, T.; Takahashi, H.; Ohta, T.; Kawai, A.; Seki, K.; Yoshida, T.; Toyama, Y.; Ichikawa, H.; Hasegawa, T. Gene expression analysis of soft tissue sarcomas: Characterization and reclassification of malignant fibrous histiocytoma. Mod. Pathol. 2007, 20, 749–759, doi:10.1038/modpathol.3800794.
[16]
Obermann, H.; Samalecos, A.; Osterhoff, C.; Schr？der, B.; Heller, R.; Kirchhoff, C. HE6, a two-subunit heptahelical receptor associated with apical membranes of efferent and epididymal duct epithelia. Mol. Reprod. Dev. 2003, 64, 13–26, doi:10.1002/mrd.10220.
[17]
Baird, K.; Davis, S.; Antonescu, C.R.; Harper, U.L.; Walker, R.L.; Chen, Y.; Glatfelter, A.A.; Duray, P.H.; Meltzer, P.S. Gene expression profiling of human sarcomas: Insights into sarcoma biology. Cancer Res. 2005, 65, 9226–9235.
[18]
Skubitz, K.M.; Francis, P.; Skubitz, A.P.; Luo, X.; Nilbert, M. Gene expression identifies heterogeneity of metastatic propensity in high-grade soft tissue sarcomas. Cancer 2012, 118, 4235–4243, doi:10.1002/cncr.26733.
[19]
Stoeckle, E.; Coindre, J.M.; Bonvalot, S.; Kantor, G.; Terrier, P.; Bonichon, F.; Nguyen Bui, B. French Federation of Cancer Centers Sarcoma Group. Prognostic factors in retroperitoneal sarcoma: A multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma Group. Cancer 2001, 92, 359–368, doi:10.1002/1097-0142(20010715)92:2<359::AID-CNCR1331>3.0.CO;2-Y.
Catton, C.N.; O’Sullivan, B.; Kotwall, C.; Cummings, B.; Hao, Y.; Fornasier, V. Outcome and prognosis in retroperitoneal soft tissue sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 1994, 29, 1005–1010, doi:10.1016/0360-3016(94)90395-6.
[22]
Kilkenny, J.W., 3rd; Bland, K.I.; Copeland, E.M., 3rd. Retroperitoneal sarcoma: The University of Florida experience. J. Am. Coll. Surg. 1996, 182, 329–339.
[23]
Karakousis, C.P.; Velez, A.F.; Gerstenbluth, R.; Driscoll, D.L. Resectability and survival in retroperitoneal sarcomas. Ann. Surg. Oncol. 1996, 3, 150–158, doi:10.1007/BF02305794.
[24]
Lewis, J.J.; Leung, D.; Woodruff, J.M.; Brennan, M.F. Retroperitoneal soft-tissue sarcoma: Analysis of 500 patients treated and followed at a single institution. Ann. Surg. 1998, 228, 355–365, doi:10.1097/00000658-199809000-00008.
[25]
Herman, K.; Grucha？a, A.; Niezabitowski, A.; Gliński, B.; Lackowska, B. Prognostic factors in retroperitoneal sarcomas: Ploidy of DNA as a predictor of clinical outcome. J. Surg. Oncol. 1999, 71, 32–35, doi:10.1002/(SICI)1096-9098(199905)71:1<32::AID-JSO7>3.0.CO;2-B.
[26]
Coindre, J.M.; Mariani, O.; Chibon, F.; Mairal, A.; de Saint Aubain Somerhausen, N.; Favre-Guillevin, E.; Bui, N.B.; Stoeckle, E.; Hostein, I.; Aurias, A. Most malignant fibrous histiocytomas developed in the retroperitoneum are dedifferentiated liposarcomas: A review of 25 cases initially diagnosed as malignant fibrous histiocytoma. Mod. Pathol. 2003, 16, 256–262, doi:10.1097/01.MP.0000056983.78547.77.
[27]
Pilotti, S.; Della Torre, G.; Lavarino, C.; Sozzi, G.; Minoletti, F.; Vergani, B.; Azzarelli, A.; Rilke, F.; Pierotti, M.A. Molecular abnormalities in liposarcoma: Role of MDM2 and CDK4-containing amplicons at 12q13-22. J. Pathol. 1998, 185, 188–190, doi:10.1002/(SICI)1096-9896(199806)185:2<188::AID-PATH53>3.0.CO;2-2.
[28]
Horvai, A.E.; Schaefer, J.T.; Nakakura, E.K.; O’Donnell, R.J. Immunostaining for peroxisome proliferator gamma distinguishes dedifferentiated liposarcoma from other retroperitoneal sarcomas. Mod. Pathol. 2008, 21, 517–524.
[29]
Haun, J.B.; Castro, C.M.; Wang, R.; Peterson, V.M.; Marinelli, B.S.; Lee, H.; Weissleder, R. Micro-NMR for rapid molecular analysis of human tumor samples. Sci. Transl. Med. 2011, 3, 71ra16, doi:10.1126/scitranslmed.3002048.
[30]
Tanas, M.R.; Sboner, A.; Oliveira, A.M.; Erickson-Johnson, M.R.; Hespelt, J.; Hanwright, P.J.; Flanagan, J.; Luo, Y.; Fenwick, K.; Natrajan, R.; et al. Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci. Transl. Med. 2011, 3, 98ra82.
[31]
Rodriguez, R.; Rubio, R.; Menendez, P. Modeling sarcomagenesis using multipotent mesenchymal stem cells. Cell Res. 2012, 22, 62–77, doi:10.1038/cr.2011.157.
[32]
Helman, L.J.; Meltzer, P. Mechanisms of sarcoma development. Nat. Rev. Cancer 2003, 3, 685–694, doi:10.1038/nrc1168.
[33]
Fodde, R.; Brabletz, T. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr. Opin. Cell Biol. 2007, 19, 150–158, doi:10.1016/j.ceb.2007.02.007.
[34]
Matushansky, I.; Hernando, E.; Socci, N.D.; Mills, J.E.; Matos, T.A.; Edgar, M.A.; Singer, S.; Maki, R.G.; Cordon-Cardo, C. Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway. J. Clin. Invest. 2007, 117, 3248–3257, doi:10.1172/JCI31377.
[35]
Fodde, R.; Brabletz, T. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr. Opin. Cell Biol. 2007, 19, 150–158, doi:10.1016/j.ceb.2007.02.007.
[36]
Matthay, K.K.; Villablanca, J.G.; Seeger, R.C.; Stram, D.O.; Harris, R.E.; Ramsay, N.K.; Swift, P.; Shimada, H.; Black, C.T.; Brodeur, G.M.; et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N. Engl. J. Med. 1999, 341, 1165–1173, doi:10.1056/NEJM199910143411601.
[37]
Rodriguez, R.; Rubio, R.; Masip, M.; Catalina, P.; Nieto, A.; de la Cueva, T.; Arriero, M.; San Martin, N.; de la Cueva, E.; Balomenos, D.; et al. Loss of p53 induces tumorigenesis in p21-deficient mesenchymal stem cells. Neoplasia 2009, 11, 397–407.
Detwiller, K.Y.; Fernando, N.T.; Segal, N.H.; Ryeom, S.W.; D’Amore, P.A.; Yoon, S.S. Analysis of hypoxia-related gene expression in sarcomas and effect of hypoxia on RNA interference of vascular endothelial cell growth factor A. Cancer Res. 2005, 65, 5881–5889, doi:10.1158/0008-5472.CAN-04-4078.
[40]
Konstantinopoulos, P.A.; Fountzilas, E.; Goldsmith, J.D.; Bhasin, M.; Pillay, K.; Francoeur, N.; Libermann, T.A.; Gebhardt, M.C.; Spentzos, D. Analysis of multiple sarcoma expression datasets: Implications for classification, oncogenic pathway activation and chemotherapy resistance. PLoS One 2010, 5, e9747.
[41]
Yuen, J.S.; Macaulay, V.M. Targeting the type 1 insulin-like growth factor receptor as a treatment for cancer. Expert Opin. Ther. Targets 2008, 12, 589–603, doi:10.1517/14728222.12.5.589.
[42]
Blay, J.Y.; Ray-Coquard, I.; Alberti, L.; Ranchère, D. Targeting other abnormal signaling pathways in sarcoma: EGFR in synovial sarcomas, PPAR-gamma in liposarcomas. Cancer Treat. Res. 2004, 120, 151–167, doi:10.1007/1-4020-7856-0_9.
[43]
Adriaenssens, E.; Vanhecke, E.; Saule, P.; Mougel, A.; Page, A.; Romon, R.; Nurcombe, V.; Le Bourhis, X.; Hondermarck, H. Nerve growth factor is a potential therapeutic target in breast cancer. Cancer Res. 2008, 68, 346–351.
[44]
Martínez-Torrecuadrada, J.; Cifuentes, G.; López-Serra, P.; Saenz, P.; Martínez, A.; Casal, J.I. Targeting the extracellular domain of fibroblast growth factor receptor 3 with human single-chain Fv antibodies inhibits bladder carcinoma cell line proliferation. Clin. Cancer Res. 2005, 11, 6280–6290, doi:10.1158/1078-0432.CCR-05-0282.
[45]
Mito, J.K.; Riedel, R.F.; Dodd, L.; Lahat, G.; Lazar, A.J.; Dodd, R.D.; Stangenberg, L.; Eward, W.C.; Hornicek, F.J.; Yoon, S.S.; et al. Cross species genomic analysis identifies a mouse model as undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma. PLoS One 2009, 4, e8075.
