Ewing Sarkom-PNET
Özet
Ewing sarkomu, çocuklarda ve genç erişkinlerde osteosarkomdan sonra en sık görülen ikinci agresif kemik malignitesidir. En yüksek insidansına 10-20 yaş aralığında ulaşan bu tümör, akciğer, kemik ve kemik iliğine erken hematojen metastaz yapma eğilimi gösterir. Genellikle kemikte, pelvis ve uzun kemiklerin diyafizinde yerleşmekle birlikte ekstraosseöz bölgelerde de ortaya çıkabilir. En belirgin klinik semptomu hızla ilerleyen şiddetli ağrıdır; ayrıca ateş, anemi ve serum LDH yüksekliği gibi bulgular eşlik edebilir. Vakaların büyük çoğunluğunda (%85) tanı kriteri olan t(11;22)(q24;q12) EWS-FLI-1 füzyon geni saptanır. Tanı aşamasında direkt grafi ve lokal yayılımı değerlendirmede MRI en güvenilir yöntemlerdir. Multimodal tedavi yaklaşımından önce sağkalım %10’un altındayken; neoadjuvan/adjuvan çok ajanlı yoğun kemoterapi (VACD, VACD-IE rejimleri) ve lokal tedavilerin (cerrahi ve radyoterapi) kombine edilmesiyle lokalize hastalıkta bu oran %60-70 seviyelerine yükselmiştir. Ancak uzak metastaz varlığı en olumsuz prognostik faktör olup metastatik vakalarda sağkalım %30 civarındadır. Geç nüksler, sekonder maligniteler ve ortopedik sorunlar hastaların yaşam kalitesini etkilediğinden, nüks oranlarını düşürecek yeni tedavi modalitelerine ve kapsamlı ortopedik rehabilitasyona ihtiyaç duyulmaktadır.
Ewing sarcoma is the second most common aggressive bone malignancy in children and young adolescents after osteosarcoma. Reaching its peak incidence between the ages of 10 and 20, this tumor exhibits a strong propensity for early hematogenous metastasis to the lungs, bones, and bone marrow. Although it primarily arises in the bones, particularly the pelvis and the diaphysis of long bones, it can also manifest in extraosseous sites. The earliest and most prominent symptom is rapidly progressing severe pain, frequently accompanied by fever, anemia, and elevated serum LDH levels. A key diagnostic hallmark found in approximately 85% of cases is the t(11;22)(q24;q12) EWS-FLI-1 fusion gene. Plain radiography and MRI are routinely utilized for primary evaluation and local staging. Before multimodal management, the long-term survival rate was under 10%; however, combining neoadjuvant/adjuvant multi-agent chemotherapy (such as VACD and VACD-IE) with local control measures (surgery and radiation) has dramatically increased survival to 60-70% for localized disease. Nevertheless, the presence of distant metastasis remains the most adverse prognostic factor, dropping the survival rate to around 30%. Since late recurrences, secondary malignancies, and orthopedic complications significantly impair quality of life, novel therapeutic modalities and structured orthopedic rehabilitation are critically required.
Referanslar
S. Ushigome, R. Machinami, P.H. Sorensen, Ewing sarcoma/ primitive neuroectodermal tumor, in: C.D.M. Fletcher, K.K. Unni, F. Mertens, (Eds.), WHO Classification of Tumors, Pathology and Genetics, Tumors of Soft Tissue and Bone, 2003.
Nesbit ME Jr, Gehan EA, Burgert EO Jr, et al. Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study. J Clin Oncol 1990; 8:1664.
Smith MAS, Gurney JG, Ries LA. Cancer in adolescents 15 to 19 years old. In: Cancer incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995, Pub #99-4649, Smith MAS, Gurney JG, Ries LA, et al (Eds), National Cancer Institute, Bethesda, MD 1999.
Jürgens H, Exner U, Gadner H, et al. Multidisciplinary treatment of primary Ewing's sarcoma of bone. A 6-year experience of a European Cooperative Trial. Cancer 1988; 61:23.5.3. Ewing J. Diffuse endothelioma of bone. Proc NY Pathol Soc 1921;21:17–24.31
Cancer Incidence and Survivalamong Children and Adolescents: United States SEER Program 1975-1995 http://seer.cancer.gov/publications/childhood/introduction.pdf (Accessed on May 31, 2011).
Bleyer A, O’Leary M, Barr R, Ries LAG. Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975-2000. NIH Pub. No. 06-5767, National Cancer Institute, Bethesda, MD 2006.
Stiller CA, Bielack SS, Jundt G, Steliarova-Foucher E. Bone tumours in European children and adolescents, 1978-1997. Report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006; 42:2124.
Birch JM, Alston RD, Kelsey AM, et al. Classification and incidence of cancers in adolescents and young adults in England 1979-1997. Br J Cancer 2002; 87:1267.
Hartley AL, Birch JM, Blair V, et al. Cancer incidence in the families of children with Ewing's tumor. J Natl Cancer Inst 1991; 83:955.
Buckley JD, Pendergrass TW, Buckley CM, et al. Epidemiology of osteosarcoma and Ewing's sarcoma in childhood: a study of 305 cases by the Children's Cancer Group. Cancer 1998; 83:1440.
Wagner MJ, Gopalakrishnan V, Ravi V, et al. Vincristine, Ifosfamide, and Doxorubicin for Initial Treatment of Ewing Sarcoma in Adults. Oncologist 2017; 22:1271.
Novakovic B, Goldstein AM, Wexler LH, Tucker MA. Increased risk of neuroectodermal tumors and stomach cancer in relatives of patients with Ewing's sarcoma family of tumors. J Natl Cancer Inst 1994; 86:1702.
Zhang J, Walsh MF, Wu G, et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 2015; 373:2336.
E. Dejana, Endothelial cell–cell junctions: happy together, Nat. Rev. Mol. Cell. Biol. 5 (2004) 261–270.
O. Delattre, J. Zucman, B. Plougastel, C. Desmaze, T. Melot, M. Peter, H. Kovar, I. Joubert, P. de Jong, G. Rouleau, et al., Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours, Nature 359 (1992) 162–165
De Alava E, Lozano MD, Patino A, Sierrasesumaga L, PardoMindan FJ. Ewing family tumors: potential prognostic value of reverse-transcriptase polymerase chain reaction detection of minmal residual disease in peripheral blood samples. Diagn Mol Pathol 1998;7:152– 7.
Van der Woude HJ, Bloem JL, Hogendoorn PC. Preoperative evaluation and monitoring chemotherapy in patients with high-grade osteogenic and Ewing’s sarcoma: review of current imaging modalities. Skeletal Radiol 1998;27:57 –71.
Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res 1980; 153:106– 20.
Musculoskeletal Sites. In: American Joint Committee on Cancer. AJCC Cancer Staging Manual, 6th edn. New York: Springer 2002;185–200.
Daldrup-Link HE, Franzius C, Link TM, Laukamp D, Sciuk J, Jurgens H, et al. Whole-body MR imaging for detection of bone metastases in children and young adults: comparison with skeletal scintigraphy and FDG PET. Am J Roentgenol 2001;177:229– 36
Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, et al. Localized Ewing tumor of bone: final results of the cooperative Ewing’s Sarcoma Study CESS 86. J Clin Oncol 2001;19:1818–29.
Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 2003;348:694–701.
Cripe TP. Ewing sarcoma: an eponym window to history. Sarcoma. 2011;2011:457532. doi:10.1155/2011/457532 (Epub 2010 Dec 1).
Bacci G, Balladelli A, Forni C, et al. Adjuvant and neoadjuvant chemotherapy for Ewing sarcoma family tumors in patients aged between 40 and 60: report of 35 cases and comparison of results with 586 younger patients treated with the same protocols in the same years. Cancer 2007; 109:780.
Schuetze SM, Patel S. Should patients with high-risk soft tissue sarcoma receive adjuvant chemotherapy? Oncologist 2009; 14:1003.
Mirzaei L, Kaal SE, Schreuder HW, Bartels RH. The Neurological Compromised Spine Due to Ewing Sarcoma. What First: Surgery or Chemotherapy? Therapy, Survival, and Neurological Outcome of 15 Cases With Primary Ewing Sarcoma of the Vertebral Column. Neurosurgery 2015; 77:718.
Gaspar N, Hawkins DS, Dirksen U, et al. Ewing Sarcoma: Current Management and Future Approaches Through Collaboration. J Clin Oncol 2015; 33:3036.
Nesbit ME Jr, Gehan EA, Burgert EO Jr, Vietti TJ, Cangir A, Tefft M, Evans R, Thomas P, Askin FB, Kissane JM, Pritchard DJ, Herrmann J, Neff J, Makley JT, Gilula L. Multimodal therapy for the management of primary, nonmetastatic Ewing’s sarcoma
De Alava E, Kawai A, Healey JH, Fligman I, Meyers PA, Huvos AG, et al. EWS/Fli1 fusion transcript structure is an independent determinant of prognosis in Ewing’s sarcoma. J Clin Oncol 1998; 16:1248– 55.
Hustu HO, Holton C, James DJr, Pinkel D. Treatment of Ewing's sarcoma with concurrent radiotherapy and chemotherapy, J Pediatr, 1968, vol. 73 (pg. 249-51)
Rosen G, Wollner N, Tan C, Wu SJ, Hajdu SI, Cham W, et al. Proceedings: disease-free survival in children with Ewing’s sarcoma treated with radiation therapy and adjuvant four-drug sequential chemotherapy. Cancer 1974;33:384–93
Nesbit ME Jr, Gehan EA, Burgert EO Jr, Vietti TJ, Cangir A, Tefft M, et al. Multimodal therapy for the management of primary, nonmetastatic Ewing’s sarcoma of bone: a long-term follow-up of the First Intergroup Study. J Clin Oncol 1990;8:1664–7
Burgert EO Jr, Nesbit ME, Garnsey LA, Gehan EA, Herrmann J, Vietti TJ, et al. Multimodal therapy for the management of nonpelvic, localized Ewing’s sarcoma of bone: intergroup study of IESS-II. J Clin Oncol 1990;8:1514–24.
urgens H, Exner U, Gadner H, Harms D, Michaelis J, Sauer R, et al. Multidisciplinary treatment of primary Ewing’s sarcoma of bone. A 6-year experience of a European Cooperative Trial. Cancer 1988;61:23– 32.
Kung FH, Pratt CB, Vega RA, Jaffe N, Strother D, Schwenn M, et al. Ifosfamide/etoposide combination in the treatment of recurrent malignant solid tumors of childhood. A Pediatric Oncology Group Phase II study. Cancer 1993;71:1898 –903.
Miser JS, Kinsella TJ, Triche TJ, Tsokos M, Jarosinski P, Forquer R, et al. Ifosfamide with Mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol 1987;5:1191–8.
Meyers PA, Krailo MD, Ladanyi M, Chan KW, Sailer SL, Dickman PS, et al. High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing’s sarcoma does not improve prognosis. J Clin Oncol 2001;19:2812 –20.
Tanaka K, Matsunobu T, Sakamoto A, Matsuda S, Iwamoto Y. High-dose chemotherapy and autologous peripheral blood stem-cell transfusion after conventional chemotherapy for patients with high-risk Ewing’s tumors. J Orthop Sci 2002;7:477 –82.
Schuck A, Ahrens S, Paulussen M, Kuhlen M, Konemann S, Rube C, et al. Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS81, CESS86 and EICESS92 trials. Int J Radiat Oncol Biol Phys 2003;55:168– 77.
Sailer SL, Harmon DC, Mankin HJ, Truman JT, Suit HD. Ewing’s sarcoma: surgical resection as a prognostic factor. Int J Radiat Oncol Biol Phys 1988;15:43 –52.
Ozaki T, Hillmann A, Hoffmann C, Rube C, Blasius S, Dunst J, Jürgens H, Winkelmann W. Significance of surgical mar[1]gin on the prognosis of patients with Ewing’s sarcoma. A report from the Cooperative Ewing’s Sarcoma Study. Cancer. 1996;78(4):892–900
Bacci G, Toni A, Avella M, Manfrini M, Sudanese A, Ciaroni D, Boriani S, Emiliani E, Campanacci M. Long-term results in 144 localized Ewing’s sarcoma patients treated with combined ther[1]apy. Cancer. 1989;63(8):1477–86.
Kawaguchi N, Ahmed AR, Matsumoto S, Manabe J, Matsushita Y. The concept of curative margin in surgery for bone and soft tissue sarcoma. Clin Orthop Relat Res. 2004;419:165–72.
Schuck A, Ahrens S, Paulussen M, Kuhlen M, Konemann S, Rube C, Winkelmann W, Kotz R, Dunst J, Willich N, Jürgens H. Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol Biol Phys. 2003;55(1):168–77
Radiat Oncol Biol Phys. 2003;55(1):168–77. 63. Paulussen M, Ahrens S, Burdach S, Craft A, Dockhorn-Dwor[1]niczak B, Dunst J, Frohlich B, Winkelmann W, Zoubek A, Jür[1]gens H. Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol. 1998;9(3):275–81.4
JOA Musculoskeletal Tumor Committee. Bone Tumor Registry in Japan. 2011.
Paulussen M, Ahrens S, Lehnert M, Taeger D, Hense HW, Wag[1]ner A, Dunst J, Harms D, Reiter A, Henze G, Niemeyer C, Gobel U, Kremens B, Folsch UR, Aulitzky WE, Voute PA, Zoubek A, Jürgens H. Second malignancies after Ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study. Ann Oncol. 2001;12(11):1619–30
