RATIONALE: The Ewing sarcoma family of malignant tumors is a group of tumors characterized by morphologically similar round-cell neoplasms and by the presence of a common chromosomal translocation; Ewing sarcoma family of tumors typically occur in children and young adults between 4 to 15 years of age. The primary tumor usually originates in the bone, extraskeletal localization is rare. PATIENT CONCERN: We present a case report concerning a 32-year-old male patient with a primary involvement of the penis. DIAGNOSIS: The histopathology from the first penile biopsy showed a small-cell neuroendocrine carcinoma; however, that result was based on a sample obtained at a different facility than the Sarcoma Center, where the investigating pathologist did not have the adequate expertise. The patient then underwent a radical penectomy and a second reading of the histology was demanded after a radical penile amputation when Ewing sarcoma with R1 resection was confirmed. INTERVENTIONS: The patient was referred to the national Sarcoma Center, where - using a multidisciplinary approach - the treatment was started with curative intent. However, it was preceded by a non-standard initiation of the therapy due to the poor primary diagnosis. OUTCOMES: The non-standard therapy at the onset of the disease caused a poor prognosis of an otherwise curable diagnosis. Despite all that, the patient survived for a relatively long time. LESSONS: The treatment of sarcomas with atypical localizations should be conducted by an experienced multidisciplinary team in a center with experience in sarcoma treatment.

Assoc Prof Clinical Trial Unit Masaryk Memorial Cancer Institute Zluty kopec 7 656 53 Brno Czech Republic And Department of Pharmacology Faculty of Medicine Masaryk University Kamenice

Assoc Prof Department of Cancer Comprehensive Care Masaryk Memorial Cancer Institute Faculty of Medicine Masaryk University Zluty kopec 7 Brno Czech Republic

Assoc Prof Department of Radiation Oncology Masaryk Memorial Cancer Institute Faculty of Medicine Masaryk University Zluty kopec

Department of Cancer Comprehensive Care Masaryk Memorial Cancer Institute Faculty of Medicine Masaryk University Zluty kopec

Department of Cancer Comprehensive Care Masaryk Memorial Cancer Institute Faculty of Medicine Masaryk University Zluty kopec 7 656 53 Brno Czech Republic And Department of Medical Ethics Faculty of Medicine Masaryk University Kamenice

Department of Cancer Comprehensive Care Masaryk Memorial Cancer Institute Zluty kopec

Department of Pathology St Anne's University Hospital Faculty of Medicine Masaryk University Pekarska

Department of Radiology Masaryk Memorial Cancer Institute Zluty kopec

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Bleyer WA, Barr RD. Bone cancer in Cancer in Adolescents and Young Adults. 2007;Verlag: Springer, 203-215.

Bleyer WA, 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. Bethesda, MD: National Cancer Institute, NIH Pub. No 06–5767; 2006. 97–109.

Cangir A, Vietti TJ, Gehan EA, et al. . Ewing's sarcoma metastatic at diagnosis: Results and comparsons of two intergroup Ewing's sarcoma studies. Cancer 1990;66:887–93. PubMed

Bernstein ML, Devidas M, Lafreniere D, et al. . Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457- a report from the Children's Oncology Group. J Clin Oncol 2006;24:152–9. PubMed

Ladenstein R, Pötschger U, Le Deley MC, et al. . Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 2010;28:3284–91. PubMed

Zoubek A, Pfleiderer C, Salzer- Kuntschik M, et al. . Variability of EWS chimeric transcripts in Ewing tumours: a comparson of clinical and molecular data. Br J Cancer 1994;70:908–13. PubMed PMC

Grünewald TGP, Cidre-Aranaz F, Surdez D, et al. . Ewing sarcoma. Nat Rev Dis Primers 2018;4:5. PubMed

Sorensen PH, Lessnick SL, Lopez- Terrada, et al. . A second Ewing's sarcoma translocation, t(21,22), fuses the EWS gene to another ETS- family transcription factor. ERG Nat Genet 1994;6:146–51. PubMed

Machado I, Noguera R, Pellin A, et al. . Molecular diagnosis of Ewing sarcoma family of tumors: a comparative analysis of 560 cases with FISCH and RT-PCR. Diagn Mol Pathol 2009;18:189–99. PubMed

Antonescu CR, Owosho AA, Zhang I, et al. . Sarcomas with CIC- rearrangements are a distinct pathologic entity with the aggressive outcome: a clinicopathologic and molecular study of 115 cases. Am J Surg Pathol 2017;41:941–9. PubMed PMC

Yamada Y, Kuda M, Kohashi K, 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. PubMed

Bacci G, Forni C, Longhi A, et al. . Long-term outcome for patients with non- metastatic Ewing's sarcoma treated with adjuvant chemotherapy: analysis of 359 patients at the Instituto Ortopedico Rizzoli. J Clin Oncol 2000;18:4–11. PubMed

Cotteril SJ, Ahrens S, Paulussen M, et al. . 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;18:3108–14. PubMed

Miser JS, Krailo MD, Tarbell NJ, et al. . Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide – a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol 2004;22:2873–6. PubMed

Schleiermacher G, Peter M, Oberlin O, et al. . Increased risk of systemic relapse associated with bone marrow micrometastasis and circulating tumor cells in localized Ewing sarcoma tumor. J Clin Oncol 2003;21:85–91. PubMed

EURO-E.W.I.N.G 99 treatment manual available online cit Oct-23-2020, Available at: http://euro-ewing.klinikum.uni-muenster.de.

EWING 2008 treatment manual available online cit Oct-23-2020, Available at: http://clinicaltrials.gov/show/NCT00987636.

Anderton J, Moroz V, Marec-Bérard P, et al. . International randomised controlled trial for the treatment of newly diagnosed EWING sarcoma family of tumours - EURO EWING 2012 Protocol. Trials 2020;21:96. PubMed PMC

Pieper S, Ranft A, Braun-Munziger G, et al. . Ewing's tumor ower the age of 40: a retrospective analysis of 47 patients treated according to the International Clinical Trials EICESS 92 and EURO-E.W.I.N.G. 99. Onkologie 2008. 657–63. PubMed

Engelhardt M, Zeiser R, Ihorst G, et al. . High-dose chemotherapy and autologous peripheral blood stem cell transplantation in adult patients with high-risk or advanced Ewing and soft tissue sarcoma. J Cancer Res Clin Oncol 2007;133:1–1. PubMed

Zapletalova D, André N, Deak L, et al. . Metronomic chemotherapy with the COMBAT regimen in advanced pediatric malignancies: a multicenter experience. Oncology 2012;82:249–60. PubMed

Penel N, Adenis A, Bocci G. Cyclophosphamide-based metronomic chemotherapy: after 10 years of experience, where do we stand and where are we going? Crit Rev Oncol Hematol 2012;82:40–50. PubMed

Cetines H, Kir G, Gelmann EP, et al. . Primary vulvar Ewing sarcoma/primitive neuroectodermal tumor: a report of 2 cases and review of the literature. Int J Gynecol Cancer 2009;19:1131–6. PubMed

Yip CM, Hsu SS, Chang NJ, et al. . Primary vaginal extraosseous Ewing sarcoma/primitive neuroectodermal tumor with cranial metastasis. J Chin Med Assoc 2009;72:332–5. PubMed

Sorensen JB, Schultze HR, Madsen EL, et al. . Primitive neuroectodermal tumor PNET) of the uterine cavity. Eur J Obst Gynecol 1998;76:181–4. PubMed

Kim KJ, Jang BW, Lee SK, et al. . A case of peripheral primitive neuroectodermal tumor of the ovary. Int J Gynecol Cancer 2004;14:370–2. PubMed

Heikaus S, Schaefer KL, Eucker J, et al. . Primary peripheral primitive neuroectodermal tumor/Ewing's tumor of the testis of a 46-year-old man – differential diagnosis and review of the literature. Hum Pathol 2009;40:893–7. PubMed

Adapa P, Chung TW, Popek EJ, et al. . Extraosseous Ewing sarcoma of the thyroid gland. Pediatr Radiol 2009;39:1365–8. PubMed

Okada Y, Kamata S, Akashi T, et al. . Primitive neuroectodermal tumor/Ewing's sarcoma of the urinary bladder: a case report and its molecular diagnosis. Int J Clin Oncol 2011;16:435–8. PubMed

Jimenez RE, Folpe AL, Lapham RL, et al. . Primary Ewing's sarcoma/primitive neuroectodermal tumor of the kidney. Am J Surg Pathol 2002;26:320–7. PubMed

Song DE, Choi GW, Davis M, et al. . Primitive neuroectodermal tumor of the gallbladder. Arch Pathol Lab Med 2004;128:571–3. PubMed

Maesava C, Iijima S, Sato N, et al. . Esophageal extraskeletal Ewing's sarcoma. Hum Pathol 2002;33:130–2. PubMed

Rafailidis S, Ballas K, Psarras K, et al. . Primary Ewing sarcoma of the stomach – a newly described entity. Eur Surg Res 2009;42:17–20. PubMed

Lee YY, Kim DH, Lee JH, et al. . Primary pulmonary Ewing's sarcoma/primitive neuroectodermal tumor in a 67-year-old man. J Korean Med Sci 2007;22: Suppl: S159–63. PubMed PMC

Siddiqui MA, Akhtar J, Shameem M, et al. . Giant extraosseous Ewing sarcoma of the lung in a young adolescent female – a case report. Acta Ortop Belg 2001;77:270–3. PubMed

Toh KL, Tan PH, Cheng WS. Primary extraskeletal Ewing's sarcoma of the external genitalia. J Urol 1999;162:159–60. PubMed

Kilicaslan I, Karayigit E, Bulut F, et al. . Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) of the penis. Int Urol Nephrol 2008;40:113–5. PubMed

Jiménez-Verdejo J, Fernández PL, Haddad A, et al. . Extraskeletal Ewing's sarcoma metastatic to penis. Br J Urol 1992;70:206–7. PubMed

Yankelevich GR, Piraino J, Edwards D, et al. . Noninvasive Ewing's sarcoma of the penis: a rare entity. Urology 2020;144:e15–8. PubMed

Sharma P, Bakshi H, Chheda Y, et al. . Primary Ewing's sarcoma of penis - a rare case report. Indian J Surg Oncol 2011;2:332–3. PubMed PMC

Ma Z, Brimo F, Zeizafoun N. Primary Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) of the penis: a report of an extraordinarily unusual site and a literature review of extraskeletal Ewing's sarcoma. Int J Surg Pathol 2013;21:63–7. PubMed

He Y, Sun N, Zhang W, et al. . Ewing sarcoma/primitive neuro-ectodermal tumor of the urogenital system in children: a retrospective observational case series. J Pediatr Urol 2019;15:556.e1-556.e7. PubMed

Casali PG, Bielack S, Abecassis N, et al. . ESMO Guidelines Committee, PaedCan and ERN EURACAN. Bone sarcomas: ESMO-PaedCan-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29: Suppl 4: iv79–95. PubMed

ERN EURACAN – Rare Adult Solid Cancers available on-line Available at: https://euracan.ern-net.eu/cit. Oct -23-2020.