oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2019-18-5-29-37oncotomsk-1185Research ArticleКЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯCLINICAL STUDIESСАРКОМА ЮИНГА: ОСОБЕННОСТИ ЛИМФОГЕННОГО МЕТАСТАЗИРОВАНИЯ И ФАКТОРЫ ПРОГНОЗАEWING SARCOMA: FEATURES OF LYMPHOGENOUS METASTASIS AND PROGNOSTIC FACTORShttps://orcid.org/0000-0002-4066-2688ВасильевН. В.VasilyevN. V.

Васильев Николай Вольтович, кандидат медицинских наук, старший научный сотрудник отделения общей и молекулярной патологии

г. Томск, 634009, пер. Кооперативный, 5

SPIN-код: 1627-5226

AuthorID (РИНЦ): 560293

Researcher ID (WOS): D-1144-2012

Author ID (Scopus): 57192110276

Nikolay V. Vasilyev, MD, PhD, Senior Researcher, Department of General and Molecular Pathology

5, Kooperativny Street, 634009-Tomsk

Researcher ID (WOS): D-1144-2012

Author ID (Scopus): 57192110276

nv-vasilev@mail.ruПолетаеваС. В.PoletaevaS. V.

Полетаева Светлана Владимировна, врач-патологоанатом патологоанатомического отделения

г. Самара, 443031, ул. Солнечная, 5

SPIN-код: 7906-1944

AuthorID (РИНЦ): 730335

Svetlana V. Poletaeva, MD, Pathoanatomical Department

50, Solnechnaya Street, 443031-Samara

ТабакаевС. А.TabakaevS. A.

г. Томск, 634009, пер. Кооперативный, 5

Stanislav A. Tabakaev, MD, Physician of the Department of Radiation Diagnostics

5, Kooperativny Street, 634009-Tomsk

ТюкаловЮ. И.TyukalovYu. I.

Тюкалов Юрий Иванович, кандидат медицинских наук, главный врач

г. Томск, 634009, пер. Кооперативный, 5

Yuri I. Tyukalov, MD, PhD, Chief Physician

5, Kooperativny Street, 634009-Tomsk

https://orcid.org/0000-0002-7633-9620ПерельмутерВ. М.PerelmuterV. M.

Перельмутер Владимир Михайлович, доктор медицинских наук, профессор, руководитель отделения общей и молекулярной патологии

г. Томск, 634009, пер. Кооперативный, 5

SPIN-код: 6252-5319

AuthorID (РИНЦ): 86909

Researcher ID (WOS): C-8227-2012

Author ID (Scopus): 8091317300

Vladimir M. Perelmutter, MD, DSc, Professor, Head of the Department of General and Molecular Pathology

5, Kooperativny Street, 634009-Tomsk

Researcher ID (WOS): C-8227-2012

Author ID (Scopus): 8091317300

Научно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр Российской академии наукРоссияCancer Research Institute, Tomsk National Research Medical Center, Russian Academy of SciencesRussian FederationСамарский областной клинический онкологический диспансерРоссияSamara Regional Clinical Cancer CenterRussian Federation2019301020191852937Copyright © Васильев Н.В., Полетаева С.В., Табакаев С.А., Тюкалов Ю.И., Перельмутер В.М., 20192019Васильев Н.В., Полетаева С.В., Табакаев С.А., Тюкалов Ю.И., Перельмутер В.М.Vasilyev N.V., Poletaeva S.V., Tabakaev S.A., Tyukalov Y.I., Perelmuter V.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/1185Актуальность

Актуальность. Лимфогенное метастазирование при саркоме Юинга – редкое и малоизученное явление, возникновение которого свидетельствует об агрессивном течении и неблагоприятном прогнозе заболевания. В настоящее время не изучен механизм развития лимфогенного метастазирования и не описаны факторы риска возникновения лимфогенных метастазов при саркоме Юинга.

Целью исследования явилось изучение особенностей опухоли, обладающих прогностическими критериями в отношении развития лимфогенных метастазов, и построение на их основе математической модели, позволяющей оценить риск появления метастазов в лимфатических узлах при саркоме Юинга.

Материал и методы

Материал и методы. Были исследованы клинические характеристики опухоли у 88 пациентов с саркомой Юинга: с наличием лимфогенных метастазов (n=8) и без лимфогенных метастазов (n=80). Установлено, что первичная опухоль во всех случаях саркомы Юинга с лимфогенными метастазами имела экстраскелетное происхождение. Изучены морфологические и иммуногистохимические признаки опухоли у 31 пациента с саркомой Юинга: с лимфогенными метастазами (n=8) и без лимфогенных метастазов (n=23).

Результаты

Результаты. Статистический анализ и сравнительная оценка характеристик иммунофенотипа и гистологического строения опухоли в двух исследуемых группах показал достоверные различия, касающиеся нескольких из них: структуры «nuclear crowding» (скученность ядер), очаговых геморрагий, ядерной нормохромазии и положительной экспрессии опухолевыми клетками цитокератинов. Вышеперечисленные признаки (кроме ядерной нормохромазии) явились основой для построения с помощью метода логистической регрессии математической модели, способной прогнозировать риск возникновения лимфогенных метастазов при саркоме Юинга.

Выводы

Выводы. Обнаруженную связь с лимфогенным метастазированием экспрессии цитокератинов можно рассматривать как косвенное подтверждение патогенетического значения мезенхимально-эпителиального перехода в механизме лимфогенного метастазирования.

Background

Background. Lymphogenous metastasis in Ewing sarcoma is a relatively rare and poorly studied event associated with aggressive clinical course and poor prognosis. Until now, no risk factors for lymphogenous metastasis in patients with Ewing sarcoma are reported.

The purpose of the study was to evaluate tumor characteristics as predictors for lymphogenous metastasis and to create a mathematical model for assessing the risk of developing lymph node metastases in patients with Ewing sarcoma.

Material and Methods

Material and Methods. Clinical characteristics of the tumor were studied in 88 patients with Ewing sarcoma: in 8 patients with lymphogenous metastasis and in 80 patients having no lymphogenous metastasis. The primary tumor in all patients with lymphogenous metastasis was found to have an extraskeletal origin. Morphological and immunohistochemical characteristics of the tumor were studied in 31 patients with Ewing sarcoma: in 8 patients with lymphogenous metastasis and in 23 patients without lymphogenous metastasis.

Results

Results. Statistical analysis and comparative evaluation of the characteristics of the immunophenotype and histological pattern of the tumor in the two studied groups showed significant differences regarding several of them: the structure of nuclear crowding (fusion of nuclei), focal hemorrhages, nuclear normochromasia, and positive expression of cytokeratins by tumor cells. The above signs (except for nuclear normochromasia) were the basis for creating a mathematical model capable of predicting the risk of lymphogenous metastases in Ewing sarcoma.

Conclusion

Conclusion. The revealed association with lymphogenous metastasis of cytokeratin expression can be considered as indirect confirmation of the pathogenetic significance of the mesenchymal-epithelial transition in the mechanism of lymphogenous metastasis.

саркома Юингалимфогенное метастазированиеклинические признакигистологические характеристикииммунофенотипфакторы прогнозаматематическая модель для прогнозированияEwing sarcomalymphogenous metastasisclinical characteristicsimmunophenotypeprognostic factorsmathematical modelReferencesFletcher C.D.M., Bridge J.A., Hogendoorn P.C.W., Mertens F. WHO Classification of Tumours of Soft Tissue and Bone. IARC: Lyon, 2013. 468 p.Fletcher C.D.M., Bridge J.A., Hogendoorn P.C.W., Mertens F. WHO Classification of Tumours of Soft Tissue and Bone. IARC: Lyon, 2013. 468 p.Unni K.K., Inwards C.Y. Dahlin’s bone tumors: General aspects and data on 10,165 cases. 6th ed. 2010. Р. 402.Unni K.K., Inwards C.Y. Dahlin’s bone tumors: General aspects and data on 10,165 cases. 6th ed. 2010. Р. 402.Sahin K., Bayram S., Salduz A. Calcaneal Ewing’s Sarcoma With Skip Metastases to Tarsals and Lymph Node Involvement: A Case Report. J Foot Ankle Surg. 2018 Jan Feb; 57(1): 162–166. doi: 10.1053/j.jfas.2017.07.002.Sahin K., Bayram S., Salduz A. Calcaneal Ewing’s Sarcoma With Skip Metastases to Tarsals and Lymph Node Involvement: A Case Report. J Foot Ankle Surg. 2018 Jan Feb; 57(1): 162–166. doi: 10.1053/j.jfas.2017.07.002.Vázquez A.C., Flores P.G., Chilla Á.H. Involvement of Mediastinal Lymph Nodes by Ewing’s Sarcoma. Arch Bronconeumol. 2017 Apr; 53(4): 215–216. doi: 10.1016/j.arbres.2016.08.003.Vázquez A.C., Flores P.G., Chilla Á.H. Involvement of Mediastinal Lymph Nodes by Ewing’s Sarcoma. Arch Bronconeumol. 2017 Apr; 53(4): 215–216. doi: 10.1016/j.arbres.2016.08.003.Pinto A., Dickman P., Parham D. Pathobiologic Markers of the Ewing Sarcoma Family of Tumors: State of the Art and Prediction of Behaviour. Sarcoma. 2011; 2011: 856190. doi: 10.1155/2011/856190.Pinto A., Dickman P., Parham D. Pathobiologic Markers of the Ewing Sarcoma Family of Tumors: State of the Art and Prediction of Behaviour. Sarcoma. 2011; 2011: 856190. doi: 10.1155/2011/856190.Devi A. Extraskeletal Ewings sarcoma of the paravertebral region with lymph node metastasis. University Journal of Pre and Para Clinical Sciences. 2016. 2(5): 1–5. doi: 10.1016/j.canlet.2006.12.009.Devi A. Extraskeletal Ewings sarcoma of the paravertebral region with lymph node metastasis. University Journal of Pre and Para Clinical Sciences. 2016. 2(5): 1–5. doi: 10.1016/j.canlet.2006.12.009.Applebaum M.A., Worch J., Matthay K.K., Goldsby R., Neuhaus J., West D.C., DuBois S.G. Clinical Features and Outcomes in Patients with Extraskeletal Ewing Sarcoma. Cancer. 2011 Jul 1; 117(13): 3027–32. doi: 10.1002/cncr.25840.Applebaum M.A., Worch J., Matthay K.K., Goldsby R., Neuhaus J., West D.C., DuBois S.G. Clinical Features and Outcomes in Patients with Extraskeletal Ewing Sarcoma. Cancer. 2011 Jul 1; 117(13): 3027–32. doi: 10.1002/cncr.25840.Llombart-Bosch A., Machado I., Navarro S., Bertoni F., Bacchini P., Alberghini M., Karzeladze A., Savelov N., Petrov S., Alvarado-Cabrero I., Mihaila D., Terrier P., Lopez-Guerrero J.A., Picci P. Histological heterogeneity of Ewing’s sarcoma/PNET: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support. Virchows Arch. 2009 Nov; 455(5): 397–411. doi: 10.1007/s00428-009-0842-7.Llombart-Bosch A., Machado I., Navarro S., Bertoni F., Bacchini P., Alberghini M., Karzeladze A., Savelov N., Petrov S., Alvarado-Cabrero I., Mihaila D., Terrier P., Lopez-Guerrero J.A., Picci P. Histological heterogeneity of Ewing’s sarcoma/PNET: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support. Virchows Arch. 2009 Nov; 455(5): 397–411. doi: 10.1007/s00428-009-0842-7.Loverro G., Resta L., Di Naro E., Caringella A.M., Mastrolia S.A., Vicino M., Tartagni M., Schonauer L.M. Conservative Treatment of Ewing’s Sarcoma of the Uterus in Young Women. Case Rep Obstet Gynecol. 2015; 2015: 871821. doi: 10.1155/2015/871821.Loverro G., Resta L., Di Naro E., Caringella A.M., Mastrolia S.A., Vicino M., Tartagni M., Schonauer L.M. Conservative Treatment of Ewing’s Sarcoma of the Uterus in Young Women. Case Rep Obstet Gynecol. 2015; 2015: 871821. doi: 10.1155/2015/871821.Machado I., Navarro S., Lopez-Guerrero J.A., Alberghini M., Picci P., Llombart-Bosch A. Epithelial marker expression does not rule out a diagnosis of Ewing’s sarcoma family of tumours. Virchows Arch. 2011 Oct; 459(4): 40914. doi: 10.1007/s00428-011-1138-2.Machado I., Navarro S., Lopez-Guerrero J.A., Alberghini M., Picci P., Llombart-Bosch A. Epithelial marker expression does not rule out a diagnosis of Ewing’s sarcoma family of tumours. Virchows Arch. 2011 Oct; 459(4): 40914. doi: 10.1007/s00428-011-1138-2.Arpaci E., Yetisyigit T., Seker M., Uncu D., Uyeturk U., Oksuzoglu B., Demirci U., Coskun U., Kucukoner M., Isıkdogan A., Inanc M., Alkis N., Ozkan M. Prognostic factors and clinical outcome of patients with Ewing’s sarcoma family of tumors in adults: Multicentric study of the Anatolian Society of Medical Oncology. Med Oncol. 2013 Mar; 30(1): 469. doi: 10.1007/s12032-013-0469-z.Arpaci E., Yetisyigit T., Seker M., Uncu D., Uyeturk U., Oksuzoglu B., Demirci U., Coskun U., Kucukoner M., Isıkdogan A., Inanc M., Alkis N., Ozkan M. Prognostic factors and clinical outcome of patients with Ewing’s sarcoma family of tumors in adults: Multicentric study of the Anatolian Society of Medical Oncology. Med Oncol. 2013 Mar; 30(1): 469. doi: 10.1007/s12032-013-0469-z.Landuzzi L., De Giovanni C., Nicoletti G., Rossi I., Ricci C., Astolfi A., Scopece L., Scotlandi K., Serra M., Bagnara G.P., Nanni P., Lollini P.-L. The Metastatic Ability of Ewing’s Sarcoma Cells Is Modulated by Stem Cell Factor and by Its Receptor c-KIT. Am J Pathol. 2000 Dec; 157(6): 212331. doi: 10.1016/S0002-9440(10)64850-X.Landuzzi L., De Giovanni C., Nicoletti G., Rossi I., Ricci C., Astolfi A., Scopece L., Scotlandi K., Serra M., Bagnara G.P., Nanni P., Lollini P.-L. The Metastatic Ability of Ewing’s Sarcoma Cells Is Modulated by Stem Cell Factor and by Its Receptor c-KIT. Am J Pathol. 2000 Dec; 157(6): 212331. doi: 10.1016/S0002-9440(10)64850-X.Pandure M., Karle R., Angerkar N., Kachewar S. Case Report Ewing’s Sarcoma/Primitive Neuroectodermal tumor of plantar aspect of foot (soft tissue) in adult female: A case report. Int J Biomed Adv Res. 2014. 05 (12): 654–657. doi: 10.7439/ijbar.Pandure M., Karle R., Angerkar N., Kachewar S. Case Report Ewing’s Sarcoma/Primitive Neuroectodermal tumor of plantar aspect of foot (soft tissue) in adult female: A case report. Int J Biomed Adv Res. 2014. 05 (12): 654–657. doi: 10.7439/ijbar.Applebaum M.A., Goldsby R., Neuhaus J., DuBois S.G. Clinical features and outcomes in patients with Ewing sarcoma and regional lymph node involvement. Pediatr Blood Cancer. 2012 Oct; 59(4): 617–20. doi: 10.1002/pbc.24053.Applebaum M.A., Goldsby R., Neuhaus J., DuBois S.G. Clinical features and outcomes in patients with Ewing sarcoma and regional lymph node involvement. Pediatr Blood Cancer. 2012 Oct; 59(4): 617–20. doi: 10.1002/pbc.24053.Васильев Н.В. Лимфогенное метастазирование сарком кости. Архив патологии. 2016; 78(4): 58–64.Vasiliev N.V. Lymph node metastasis of osteosarcomas. Archive of Pathology. 2016; 78(4): 58–64. (in Russian).Leavey P.J., Collier A.B. Ewing sarcoma: prognostic criteria, outcomes and future treatment. Expert Rev Anticancer Ther. 2008 Apr; 8(4): 617–24. doi: 10.1586/14737140.8.4.617.Leavey P.J., Collier A.B. Ewing sarcoma: prognostic criteria, outcomes and future treatment. Expert Rev Anticancer Ther. 2008 Apr; 8(4): 617–24. doi: 10.1586/14737140.8.4.617.Lee Y.T., Moore T.M., Schwinn C.P. Metastasis of sarcomatous lesion in regional lymph node. J Surg Oncol. 1982 May; 20(1): 53–8. doi: 10.1002/jso.2930200113.Lee Y.T., Moore T.M., Schwinn C.P. Metastasis of sarcomatous lesion in regional lymph node. J Surg Oncol. 1982 May; 20(1): 53–8. doi: 10.1002/jso.2930200113.Hamidi N., Esen B., Kıvrak H., Sertçelik A., Gülpınar Ö. A large and metastatic primitive neuroectodermal tumor of the kidney. Turk J Urol. 2015 Sep; 41(3): 152–4. doi: 10.5152/tud.2015.92653.Hamidi N., Esen B., Kıvrak H., Sertçelik A., Gülpınar Ö. A large and metastatic primitive neuroectodermal tumor of the kidney. Turk J Urol. 2015 Sep; 41(3): 152–4. doi: 10.5152/tud.2015.92653.Huh J., Kim K.W., Park S.J., Kim H.J., Lee J.S., Ha H.K., Tirumani S.H., Ramaiya N.H. Imaging Features of Primary Tumors and Metastatic Patterns of the Extraskeletal Ewing Sarcoma Family of Tumors in Adults: A 17-Year Experience at a Single Institution. Korean J Radiol. 2015 JulAug; 16(4): 783–90. doi: 10.3348/kjr.2015.16.4.783.Huh J., Kim K.W., Park S.J., Kim H.J., Lee J.S., Ha H.K., Tirumani S.H., Ramaiya N.H. Imaging Features of Primary Tumors and Metastatic Patterns of the Extraskeletal Ewing Sarcoma Family of Tumors in Adults: A 17-Year Experience at a Single Institution. Korean J Radiol. 2015 JulAug; 16(4): 783–90. doi: 10.3348/kjr.2015.16.4.783.Miller M.E., Emerson L., Clayton F., Bentz B.G., Data R.E., Salzman K.L., Smith L. M., Yu M.K. Extraosseous Ewing’s Sarcoma. J Clin Oncol. 2007 Oct 20; 25(30): 4845–8.Miller M.E., Emerson L., Clayton F., Bentz B.G., Data R.E., Salzman K.L., Smith L. M., Yu M.K. Extraosseous Ewing’s Sarcoma. J Clin Oncol. 2007 Oct 20; 25(30): 4845–8.Tan Y., Zhang H., Ma G.-L., Xiao E.-H., Wang X.-C. Peripheral primitive neuroectodermal tumor: Dynamic CT, MRI and clinicopathological characteristics analysis of 36 cases and review of the literature. Oncotarget. 2014 Dec 30; 5(24): 12968–77. doi: 10.18632/oncotarget.2649.Tan Y., Zhang H., Ma G.-L., Xiao E.-H., Wang X.-C. Peripheral primitive neuroectodermal tumor: Dynamic CT, MRI and clinicopathological characteristics analysis of 36 cases and review of the literature. Oncotarget. 2014 Dec 30; 5(24): 12968–77. doi: 10.18632/oncotarget.2649.Zhang K., Lu R., Zhang P., Shen S., Li X. Askin’s tumor: 11 cases and a review of the literature. Oncol Lett. 2016 Jan; 11(1): 253–256. doi: 10.3892/ol.2015.3902.Zhang K., Lu R., Zhang P., Shen S., Li X. Askin’s tumor: 11 cases and a review of the literature. Oncol Lett. 2016 Jan; 11(1): 253–256. doi: 10.3892/ol.2015.3902.Cotterill S.J., Ahrens S., Paulussen M., Jürgens H.F., Voûte P.A., Gadner H., Craft A.W. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European intergroup cooperative Ewing’s sarcoma study group. J Clin Oncol. 2000 Sep; 18(17): 3108–14. doi: 10.1200/JCO.2000.18.17.3108.Cotterill S.J., Ahrens S., Paulussen M., Jürgens H.F., Voûte P.A., Gadner H., Craft A.W. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European intergroup cooperative Ewing’s sarcoma study group. J Clin Oncol. 2000 Sep; 18(17): 3108–14. doi: 10.1200/JCO.2000.18.17.3108.Франк Г.А., Завалишина Л.Э., Андреева Ю.Ю. Методы иммуногистохимии и гибридизации in situ в онкоморфологии. М., 2009. 14 c.Frank G.A., Zavalishina L.E., Andreeva Yu.Yu. Methods of immunohistochemistry and in situ hybridization in oncomorphology. Moscow, 2009. 14 p. (in Russian).Dabbs D.J. Diagnostic immunohistochemistry: theranostic and genomic. Saunders, 2010. P. 941.Dabbs D.J. Diagnostic immunohistochemistry: theranostic and genomic. Saunders, 2010. P. 941.De Silva M.V.C., McMahon A.D., Paterson L., Reid R. Identification of poorly differentiated synovial sarcoma: a comparison of clinicopathological and cytogenetic features with those of typical synovial sarcoma. Histopathology. 2003, 43 (3): 220–230. doi: 10.1046/j.13652559.2003.01668.x.De Silva M.V.C., McMahon A.D., Paterson L., Reid R. Identification of poorly differentiated synovial sarcoma: a comparison of clinicopathological and cytogenetic features with those of typical synovial sarcoma. Histopathology. 2003, 43 (3): 220–230. doi: 10.1046/j.13652559.2003.01668.x.Fisher C. Low-grade Sarcomas with CD34-Positive Fibroblasts and Low-Grade Myofibroblastic Sarcomas. Ultrastruct Pathol. 2004 SepDec; 28(5–6): 291–305. doi: 10.1080/019131290882187.Fisher C. Low-grade Sarcomas with CD34-Positive Fibroblasts and Low-Grade Myofibroblastic Sarcomas. Ultrastruct Pathol. 2004 SepDec; 28(5–6): 291–305. doi: 10.1080/019131290882187.Weinreb I., Goldstein D., Perez-Ordoñez B. Primary extraskeletal Ewing family tumor with complex epithelial differentiation: a unique case arising in the lateral neck presenting with Horner syndrome. Am J Surg Pathol. 2008 Nov; 32(11): 1742–8. doi: 10.1097/PAS.0b013e3181706252.Weinreb I., Goldstein D., Perez-Ordoñez B. Primary extraskeletal Ewing family tumor with complex epithelial differentiation: a unique case arising in the lateral neck presenting with Horner syndrome. Am J Surg Pathol. 2008 Nov; 32(11): 1742–8. doi: 10.1097/PAS.0b013e3181706252.Greco M.A., Steiner G.C., Fazzini E. Ewing’s Sarcoma with Epithelial Differentiation: Fine Structural and Immunocytochemical Study. Ultrastruct Pathol. 1988 May-Jun; 12(3): 317–25. doi: 10.3109/01913128809098044.Greco M.A., Steiner G.C., Fazzini E. Ewing’s Sarcoma with Epithelial Differentiation: Fine Structural and Immunocytochemical Study. Ultrastruct Pathol. 1988 May-Jun; 12(3): 317–25. doi: 10.3109/01913128809098044.Gu M., Antonescu C. R., Guiter G., Huvos A. G., Ladanyi M., Zakowski M.F. Cytokeratin immunoreactivity in Ewing’s sarcoma: prevalence in 50 cases confirmed by molecular diagnostic studies. Am J Surg Pathol. 2000 Mar; 24(3): 410–6.Gu M., Antonescu C. R., Guiter G., Huvos A. G., Ladanyi M., Zakowski M.F. Cytokeratin immunoreactivity in Ewing’s sarcoma: prevalence in 50 cases confirmed by molecular diagnostic studies. Am J Surg Pathol. 2000 Mar; 24(3): 410–6.Schuetz A.N., Rubin B.P., Goldblum J.R., Shehata B., Weiss S.W., Liu W., Wick M.R., Folpe A.L. Intercellular junctions in Ewing sarcoma/ primitive neuroectodermal tumor: additional evidence of epithelial differentiation. Mod Pathol. 2005 Nov; 18(11): 1403–10. doi: 10.1038/modpathol.3800435.Schuetz A.N., Rubin B.P., Goldblum J.R., Shehata B., Weiss S.W., Liu W., Wick M.R., Folpe A.L. Intercellular junctions in Ewing sarcoma/ primitive neuroectodermal tumor: additional evidence of epithelial differentiation. Mod Pathol. 2005 Nov; 18(11): 1403–10. doi: 10.1038/modpathol.3800435.Vakar-Lopez F., Ayala A.G., Raymond A.K., Czerniak B. Epithelial Phenotype in Ewing’s Sarcoma/Primitive Neuroectodermal Tumor. Int. J. Surg. Pathol. 2000. 8 (1): 59–65. doi: 10.1177/106689690000800111.Vakar-Lopez F., Ayala A.G., Raymond A.K., Czerniak B. Epithelial Phenotype in Ewing’s Sarcoma/Primitive Neuroectodermal Tumor. Int. J. Surg. Pathol. 2000. 8 (1): 59–65. doi: 10.1177/106689690000800111.Olsen S.H., Thomas D.G., Lucas D.R. Cluster analysis of immunohistochemical profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma. Mod Pathol. 2006 May; 19(5): 659–68. doi: 10.1038/modpathol.3800569.Olsen S.H., Thomas D.G., Lucas D.R. Cluster analysis of immunohistochemical profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma. Mod Pathol. 2006 May; 19(5): 659–68. doi: 10.1038/modpathol.3800569.Elbashier S.H.A., Nazarina A.R., Looi L.M. Cytokeratin immunoreactivity in Ewing sarcoma/primitive neuroectodermal tumour. Malaysian J Pathol. 2013; 35 (2): 139–145.Elbashier S.H.A., Nazarina A.R., Looi L.M. Cytokeratin immunoreactivity in Ewing sarcoma/primitive neuroectodermal tumour. Malaysian J Pathol. 2013; 35 (2): 139–145.

The authors declare that there are no conflicts of interest present.