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Pediatrics and Neonatology (2014) xx, 1e4

Available online at www.sciencedirect.com

ScienceDirect journal homepage: http://www.pediatr-neonatol.com

CASE REPORT

Congenital Ewing’s Sarcoma/Peripheral Primitive Neuroectodermal Tumor: A Case Report and Review of the Literature Shu-Guang Jin*, Xiao-Ping Jiang, Lin Zhong Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu 610041, China Received May 26, 2013; received in revised form Oct 9, 2013; accepted Nov 2, 2013

Key Words diagnosis; Ewing’s sarcoma; newborn; peripheral primitive neuroectodermal tumor; prognosis; treatment

Ewing’s sarcoma (EWS) and peripheral primitive neuroectodermal tumor (pPNET) are small round cell malignancies that develop in soft tissue and bone. They very rarely affect newborns. A diagnosis of EWS/pPNET depends mainly on immunohistochemistry and molecular/genetic assays. Since these tumors are highly aggressive, patient prognosis is typically very poor, and treatment remains a challenge. Here, we report a 13-day-old newborn diagnosed with congenital EWS/pPNET and describe its treatment. Copyright ª 2014, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.

1. Introduction

2. Case report

Ewing’s sarcoma (EWS) and peripheral primitive neuroectodermal tumor (pPNET) are two types of malignant tumor that are histologically characterized by the presence of small, round cells in soft tissues and bone.1 This rare malignancy occurs primarily in children and adolescents, but it is extremely rare in newborns. Here, we describe a 13-day-old newborn diagnosed with EWS/pPNET in her upper left arm.

A 13-day-old newborn female was admitted due to a swollen mass on her upper-left arm after birth. She was a full-term cesarean neonate without a family history of genetic diseases. A physical examination revealed a round, soft, dark mass with clear boundaries, measuring about 5 cm  5 cm  4 cm, in her upper left arm. There was no increase in local skin temperature or any detectable fluctuation. An ultrasound showed a well-defined isoechoic mass close to the brachial artery with point-like blood flow within the mass, and rich blood flow surrounding the mass. Computed tomography (CT) detected an isodense soft tissue mass measuring 4.6 cm  3.7 cm in the coronal maximum of her upper left arm, which was attached to the biceps and triceps (Figure 1). Enhanced scanning further showed a heterogeneously enhanced mass pressing onto the

* Corresponding author. Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu 610041, China. E-mail address: [email protected] (S.-G. Jin).

1875-9572/$36 Copyright ª 2014, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.pedneo.2013.11.002

Please cite this article in press as: Jin S-G, et al., Congenital Ewing’s Sarcoma/Peripheral Primitive Neuroectodermal Tumor: A Case Report and Review of the Literature, Pediatrics and Neonatology (2014), http://dx.doi.org/10.1016/j.pedneo.2013.11.002

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Figure 1 Computed tomography detects a mass present in the upper left arm.

left brachial artery, with branches of the brachial artery extending within the mass. The bone in the left humerus did not appear to be affected. The mass was completely resected and, upon gross inspection, had the appearance of a fish-like cut surface. A

S.-G. Jin et al pathologic examination found histological evidence of malignant, small round tumor cells that were not accompanied by a margin of residual tumor cells (Figure 2). The tumor cells were immunohistochemically positive for CD99 (Figure 2) and Ki67 (40%; Figure 2), and negative for desmin, myogenin, synaptophysin, leukocyte common antigen, S-100 protein, P63 protein, smooth muscle antibody, and epithelial membrane antigen. To detect chromosome 22q12 translocation, fluorescence in situ hybridization (FISH) was employed using LSI EWSR1 (22q12) Dual Color, Break Apart Rearrangement Probe (Vysis; Abbott Molecular, Des Plaines, IL, USA). Fluorescence was detected using a microscope with a Y-Fl Epi-Fluorescence Attachment (Nikon, Tokyo, Japan). Tumor cell nuclei that exhibited a split of signal pair were scored as positive for translocation and rearrangement of chromosome 22q12 (Figure 2). After surgery, enhanced chest CT and abdominal ultrasonography were performed. No evidence of abnormality or metastasis was detected. However, it was recommended that the upper left limb be amputated. The patient’s parents refused, and the infant was transferred to the oncology department for further treatment 7 days after surgery. Due to the infant’s young age and the immaturity of her organs, she received four courses of chemotherapy with cisplatin (20 mg/m2.day, quaque die  4 days, once every 3 weeks) and cyclophosphamide (0.2/ m2$d, qd  4 days, once every 3 weeks). However, 3 months later, distant metastasis involving the lung and liver were detected without local recurrence. Gradually, the infant became emaciated and infirm, and eventually she died of dyscrasia.

Figure 2 (A) A uniform population of small round cells with minimal cytoplasm and fine granular chromatin nuclei stained with hematoxylin and eosin (magnification, 300). (B) Neoplastic cells with strong expression of CD99 (En Vision; magnification, 300). (C): Expression of Ki67 (40%; En Vision; magnification, 300). (D) Fluorescence in situ hybridization reveals that tumor cells are characterized by one fused, one red, and one green signal pattern (labeled with lines), and chromosome translocations of the EWSR1 region have occurred in 22/50 nuclei.

Please cite this article in press as: Jin S-G, et al., Congenital Ewing’s Sarcoma/Peripheral Primitive Neuroectodermal Tumor: A Case Report and Review of the Literature, Pediatrics and Neonatology (2014), http://dx.doi.org/10.1016/j.pedneo.2013.11.002

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Congenital EWS/pPNET

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Table 1 Previous reports of congenital Ewing’s sarcoma and peripheral primitive neuroectodermal tumor of soft tissue in newborns. Authors 8

Naidu et al Lim et al9 Daw et al10 Smith et al11 Sebire et al12 Sebire et al12 Sebire et al12 El Hayek et al13 Saito et al14 Meazza et al15 Rosa et al16 Krenova et al17 Atla et al18

Date

Age

Sites

Treatments

Prognosis

1989 1994 1997 1998 2002 2002 2002 2004 2008 2008 2009 2011 2011

Birth Birth Birth Birth Birth 8d 16 d Birth 7d Birth Birth 3 wk Birth

Forehead Right lower eyelid Hand Skin Back Forearm Neck Hand Retroperitoneum Abdomen Neck Retroperitoneum Chest wall

Chemotherapy Surgery þ chemotherapy Chemotherapy Surgery þ chemotherapy þ others Surgery þ chemotherapy Radiotherapy Chemotherapy Surgery þ chemotherapy Chemo-radiotherapy Chemotherapy None Chemotherapy None

Alive 1 y Died Died 15 mo Died 8 y Alive Died after 1 wk Died after 6 mo Died 2.5 y Survived 2 y and 10 mo Died 25 d Died 14 h after birth Died 4 mo Died immediately after birth

3. Discussion EWS and PNET are both small round cell malignancies that develop in soft tissue and bone. These tumors originate from the neuroectoderm and are composed of undifferentiated, or poorly differentiated, neuroepithelial cells that have the capacity to differentiate into neuronal, neuroglial, or other mesenchymal cell types.2 PNET and EWS exhibit differences in their level of cell differentiation. Accordingly, PNET and EWS are considered two distinct tumor types. However, immunohistochemistry, electron microscopy, and genetic pathology have demonstrated that EWS of bone and extraskeletal tissue, PNET, and Askin’s tumor are all EWS/PNET tumors.3,4 Furthermore, the treatment and prognosis for each of these diseases is essentially identical. In addition, based on the site of origination, PNETs are classified as central or peripheral. Four percent of EWS/pPNET cases involve soft tissue sarcomas. Moreover, although 70e80% of patients experience tumor onset prior to the age of 20 years, 14% of EWS/ pPNET cases involve children younger than 5 years.5 The most common symptoms are local pain and a swollen mass, accompanied by fever or a deteriorating condition. Elevated leukocyte counts and erythrocyte sedimentation rate are also frequently observed. Imaging methods typically show no specific signs, leaving EWS/pPNET to be diagnosed based on histopathological and immunohistochemical characteristics. In addition, 90% of patients show reciprocal chromosomal translocations and fused genes (e.g., the fusion of the EWS gene on chromosome 22q12 with the FLI-1 gene on chromosome 11). The presence of this chromosome translocation combined with positive immunostaining of CD99 represent the sensitive and specific assays that are currently available for establishing a diagnosis of EWS/pPNET.6 At present, the treatment of choice for patients with EWS/pPNET consists of radical surgical resection followed by chemoradiotherapy. However, due to the highly malignant and aggressive phenotype of these tumors, approximately 25% of patients present with distant metastasis at the time of diagnosis, making it difficult to completely resect all of the tumor tissue present.7

EWS/pPNET tumors are extremely rare in newborns. To date, only 13 newborns (28 days) with congenital EWS/ pPNET of soft tissue have been reported in the English literature (Table 1). In all of these reports, the prognosis was very poor, and most of the infants did not survive more than 2 years. Consequently, judicious fetal screening is extremely important. Furthermore, when a fetal soft tissue mass is revealed by prenatal ultrasound, EWS/pPNET should be suspected. A mass puncture is necessary and will allow an immunohistochemistry examination to be performed in combination with assays to detect chromosome translocations. These results will be useful for a diagnosis of EWS/pPNET, and they can differentiate it from other conditions. If screening is performed as needed, there should be a reasonable intervention timely involving radical resection in the fetal period.

Conflicts of interest All contributing authors declare no conflicts of interest.

References 1. Desai SS, Jambhekar NA. Pathology of Ewing’s sarcoma/PNET: current opinion and emerging concepts. Indian J Orthop 2010; 44:363e8. 2. Rorke LB. The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 1983;42:1e15. 3. Gu M, Antonescu CR, Guiter G, Huvos AG, Ladanyi M, Zakowski MF. Cytokeratin immunoreactivity in Ewing’s sarcoma: prevalence in 50 cases confirmed by molecular diagnostic studies. Am J Surg Pathol 2000;24:410e6. 4. Granowetter L, West DC. The Ewing’s sarcoma family of tumors: Ewing’s sarcoma and peripheral primitive neuroectodermal tumor of bone and soft tissue. Cancer Treat Res 1997;92:253e308. 5. Coffin CM, Dehner LP. Neurogenic tumors of soft tissue. In: Coffin CM, Dehner LP, O’Shea PA, editors. Pediatric soft tissue tumors. Baltimore: Lippincott, Williams and Wilkins; 1997. p. 108e16. 6. Vural C, Uluoglu O, Akyu ¨rek N, Oguz A, Karadeniz C. The evaluation of CD99 immunoreactivity and EWS/FLI1

Please cite this article in press as: Jin S-G, et al., Congenital Ewing’s Sarcoma/Peripheral Primitive Neuroectodermal Tumor: A Case Report and Review of the Literature, Pediatrics and Neonatology (2014), http://dx.doi.org/10.1016/j.pedneo.2013.11.002

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S.-G. Jin et al translocation by fluorescence in situ hybridization in central PNETs and Ewing’s sarcoma family of tumors. Pathol Oncol Res 2011;17:619e25. Marec-Be ´rard P, Chotel F, Claude L. PNET/Ewing tumours: current treatments and future perspectives. Bull Cancer 2010; 97:707e13 [Article in French]. Naidu MRC. Primary Ewing’s tumor of the skull at birth. Indian J Pediatr 1989;56:541e3. Lim TC, Tan WT, Lee YS. Congenital extraskeletal Ewing’s sarcoma of the face: a case report. Head Neck 1994;16:75e8. Daw JL, Wiedrich TA, Bauer BS. Congenital primitive neuroectodermal tumor of the hand: a case report. J Hand Surg Am 1997;22:743e6. Smith LM, Adams RH, Brothman AR, Vanderhooft SL, Coffin CM. Peripheral primitive neuroectodermal tumor presenting with diffuse cutaneous involvement and 7; 22 translocation. Med Pediatr Oncol 1998;30:357e63. 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;5:579e86.

13. El Hayek M, Trad O, Islam S. Congenital peripheral primitive neuroectodermal tumor refractory to treatment. J Pediatr Hematol Oncol 2004;26:770e2. 14. Saito Y, Matsuzaki A, Suminoe A, Koga Y, Kurata H, Oda Y, et al. Congenital Ewing sarcoma in retroperitoneum with multiple metastases. Pediatr Blood Cancer 2008;51:698e701. 15. Meazza C, Ferrari A, Fumagalli M, Collini P, Casanova M, Pugni L, et al. A case of congenital peripheral primitive neuroectodermal tumor presenting with multiple metastases. J Pediatr Hematol Oncol 2008;30:36e8. 16. Rosa M, Mohammadi A, Campos M, Garcı´a-Garcı´a I, CorreaRivas MS. Congenital EWS/pPNET presenting as a neck mass. Pediatr Blood Cancer 2009;53:678e9. 17. Krenova Z, Kren L, Blatny J, Falk M, Kazakov DV, Grossmann P, et al. Extraosseal Ewing sarcoma as a rare cause of the blueberry muffin baby syndrome: a case report and the review of the literature. Am J Dermatopathol 2011; 33:733e5. 18. Atla B, Prasad BS, Sri KS, Vandana G. Congenital extraskeletal Ewing’s sarcoma of chest wallda rare case report. Indian J Pathol Microbiol 2011;54:803e5.

Please cite this article in press as: Jin S-G, et al., Congenital Ewing’s Sarcoma/Peripheral Primitive Neuroectodermal Tumor: A Case Report and Review of the Literature, Pediatrics and Neonatology (2014), http://dx.doi.org/10.1016/j.pedneo.2013.11.002

Peripheral Primitive Neuroectodermal Tumor: A Case Report and Review of the Literature.

Ewing's sarcoma (EWS) and peripheral primitive neuroectodermal tumor (pPNET) are small round cell malignancies that develop in soft tissue and bone. T...
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