Primary Ewing Sarcoma of the urinary bladder in an adolescent: a case report of successful organ preservation with multimodal therapy

Abstract

Introduction and importance:

Primary bladder sarcomas, particularly Ewing Sarcoma/primitive neuroectodermal tumor (ES/PNET), are exceptionally rare in the pediatric and adolescent population, presenting diagnostic and therapeutic challenges.

Case presentation:

A 15-year-old Syrian girl from a rural area, presented with lower abdominal pain and gross hematuria. Examination revealed suprapubic tenderness. Computed tomography identified a bladder dome mass and a subsequent image-guided biopsy confirmed ES/PNET. The patient received eight cycles of neoadjuvant chemotherapy, which led to significant regression on post-chemotherapy magnetic resonance imaging. Partial cystectomy with 2-cm margins was performed, followed by primary bladder closure. Pathology confirmed pathological complete response, showing no viable tumor (inflammatory changes, urothelial hyperplasia, necrosis, and fibrosis). Adjuvant radiotherapy was administered, and the patient is currently completing adjuvant chemotherapy. Surveillance imaging and cystoscopy 2 months post-operatively showed no evidence of recurrent disease.

Clinical discussion:

The rarity of bladder ES/PNET presents a therapeutic challenge. This case aligns with emerging evidence that neoadjuvant chemotherapy can be highly effective, facilitating less radical surgery. This strategy successfully avoided radical cystectomy, thereby preventing the associated long-term complications of urinary diversion. The addition of adjuvant radiotherapy was motivated by the initial presence of extensive soft tissue invasion and borderline lymph nodes, aiming to optimize local control.

Conclusion:

Multimodal therapy with neoadjuvant chemotherapy followed by adjuvant chemotherapy and radiotherapy can facilitate bladder preservation in pediatric bladder ES/PNET without compromising oncological outcomes. This strategy can mitigate the long-term morbidity of radical surgery.

Introduction

Ewing sarcoma (ES) is an aggressive sarcoma of bone and/or soft tissue with a peak incidence during adolescence and young adulthood^[1^]. The ES family of tumors encompasses three main types: ES of the bone, extra-osseous (extra skeletal) ES and primitive neuroectodermal tumor (PNET)^[2^]. PNET can rarely occur in visceral organs such as the urinary bladder. The differential diagnosis for PNET of the bladder includes rhabdomyosarcoma (RMS), lymphoid neoplasms, neuroendocrine carcinoma, and melanoma^[3^]. Immunohistochemical staining aids the diagnosis, with most PNETs demonstrating strong positivity for CD99^[4^]. Due to the rarity of these tumors, standardized treatment protocols have not been established, highlighting the importance of documenting individual cases. In line with the SCARE criteria^[5^], we present a case of ES/PNET of the urinary bladder in a 15-year-old female, emphasizing diagnostic challenges and therapeutic approaches.

HIGHLIGHTS

• Primary Ewing Sarcoma of the bladder is an exceptionally rare malignancy.

• Neoadjuvant chemotherapy enabled successful partial cystectomy, avoiding radical surgery.

• Multimodal therapy can preserve quality of life without compromising oncological outcomes.

Case presentation

A 15-year-old adolescent girl from a rural area in Syria presented in early 2024 with a chief complaint of progressive lower abdominal pain associated with intermittent gross hematuria. Physical examination was notable only for suprapubic tenderness, and no lymphadenopathy or palpable masses were found. Initial computed tomography (CT) with contrast revealed a large, irregular, heterogeneous mass measuring approximately 8.5 × 9 cm, filling most of the bladder lumen. The mass contained cystic, necrotic areas, and soft-tissue components. Initial histopathology from a bladder lavage was reported as a high-grade suburothelial sarcoma, but this sample was deemed insufficient for definitive diagnosis. A subsequent image-guided biopsy was performed. Histopathological examination revealed a small round blue cell tumor (Fig. 1). Immunohistochemistry was critical for diagnosis, showing positive for CD99 and FLI-1, and negative for myogenin, desmin, WT1, CK, and CD45 (Fig. 2) .These findings confirmed the diagnosis of ES of the urinary bladder molecular studies (fluorescence in situ hybridization or reverse transcription polymerase chain reaction) for the characteristic *EWSR1-FLI1* fusion were not performed due to resource constraints. The magnetic resonance imaging (MRI) of pelvis confirmed a large, lobulated mass within the bladder originated from the bladder dome and demonstrated clear posterior wall infiltration, extending into the perivesical fat and a few borderline-sized lymph nodes (8 mm) were noted in the external iliac chains. A whole-body bone scan and bone marrow aspiration/biopsy were performed and found to be normal, confirming localized disease. [18F]FDG PET-CT was not utilized during initial staging. This was a multidisciplinary decision based on a combination of technical limitations and clinical priorities. The primary considerations were the limited sensitivity of the available PET scanner for sub-centimeter lymph nodes, potential delays in securing an appointment, and the overarching need to rapidly initiate systemic therapy in a symptomatic patient. Following a multidisciplinary board decision, the patient started therapy as per the Children’s Oncology Group protocol AEWS0031, with interval-compressed chemotherapy^[6,7^]. The protocol involves 14 cycles of alternating vincristine–doxorubicin–cyclophosphamide (VDC) with cycles of ifosfamide–etoposide (IE). In each cycle of VDC, vincristine is administered at 1.5 mg/m² (maximum 2 mg) on the first day, cyclophosphamide is administered at 1200 mg/m² on the first day, and doxorubicin is given at 37.5 mg/m² on days 1 and 2. In each cycle of IE, etoposide is administered at 100 mg/m² on days 1 through 5, and ifosfamide is administered at 1800 mg/m² on days 1 through 5. After eight cycles of the VDC/IE regimen (vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide), a follow-up MRI demonstrated an excellent response, with the tumor regressing to 2.4 × 2.0 × 2.4 cm (Fig. 3). The previously noted borderline external iliac lymph nodes were no longer visible. The patient underwent diagnostic cystoscopy, which confirmed the presence of a solitary mass arising from the bladder dome. The remainder of the bladder walls appeared normal with healthy overlying mucosa. Based on these findings, she successfully underwent an open partial cystectomy with 2-cm margins (Fig. 4). The final surgical pathology report confirmed a pathological complete response (pCR) with no viable tumor, showing only treatment-related changes (necrosis, fibrosis, and inflammation). In the postoperative multidisciplinary tumor board meeting, due to the initial extensive spread of the tumor to nearby soft tissue components and the possibility of lymph node involvement, a decision was made to administer adjuvant radiotherapy at a cumulative dose of 45 Gy. The potential acute and long-term effects of radiotherapy, including the impact on ovarian function and fertility, were extensively discussed with the patient and her family. Ovarian transposition (oophoropexy) was presented as a potential fertility preservation strategy prior to pelvic radiotherapy. However, this procedure would have necessitated a separate surgical intervention. After comprehensive counseling regarding the benefits, risks, and procedural details, the family declined this additional surgical procedure. Written informed consent for radiotherapy was obtained from the parents, along with verbal assent from the patient. She is currently undergoing adjuvant chemotherapy and radiotherapy with good tolerance. Surveillance imaging 2 months postoperatively showed no evidence of recurrent disease. A concurrent surveillance cystoscopy was performed that revealed a well-healed surgical site at the bladder dome. The mucosa appeared intact and normal, with no evidence of residual mass, mucosal irregularity, or signs of local recurrence.

Figure 1.

Histopathological examination of the bladder mass biopsy (H&E stain) revealing a small round blue cell tumor with mitotic activity.

Figure 2.

Immunohistochemical studies show the tumor cells to be diffusely positive for CD99 (membranous) and Fli-1 (nuclear), while they are negative for cytokeratin, myogenin, desmin, WT-1, and CD45.

Figure 3.

Follow-up MRI of the pelvis after eight cycles of neoadjuvant chemotherapy (VDC/IE regimen) demonstrating significant tumor regression.

Figure 4.

The surgical specimen showing the resected bladder dome mass with 2-cm margins.

Discussion

ES/PNETs are aggressive in nature and may occur within visceral organs such as the liver, uterus, parotid gland, kidney, pancreas, and urinary bladder^[8^]. Primary urinary bladder PNET is extremely rare and patients with bladder PNET were older than those diagnosed in other organs^[9^]. Analyzing the literature, which include the 40 reported cases summarized in Table 1, provides valuable insights into clinical characteristics, treatment responses, and outcomes associated with this malignancy. The median age of patients 30 years, with a range from newborns to 81 years. The present case of a 15-year-old girl is younger than most reported cases, which typically involve older patients. Tumor sizes across reported cases range from 1 to 15 cm, with a mean size of approximately 6.8 cm. The bladder dome is the most common site of occurrence. The diagnostic work-up remains challenging due to histopathological overlap with other small round blue cell tumors, supporting the critical role of immunohistochemistry (CD99 and FLI-1 positivity) and molecular confirmation of the pathognomonic EWSR1 gene rearrangement. The analysis of the all cases reveals that surgical management is a cornerstone, with partial cystectomy performed in 15 cases (37.5%) and radical cystectomy in 16 cases (40%). The choice of procedure is often dictated by tumor size, location, and response to neoadjuvant therapy. This case, in concordance with others, underscores that a significant response to neoadjuvant chemotherapy can facilitate successful organ preservation via partial cystectomy. The presence of metastasis at diagnosis continues to be the most significant negative prognostic factor, dramatically shortening survival. This case exemplifies a successful application of a bladder-preserving strategy. The patient’s large tumor showed an excellent response to neoadjuvant VDC/IE chemotherapy, regressing from 9 to 2.4 cm, which enabled a subsequent partial cystectomy. The finding of a pCR in the surgical specimen is a highly favorable outcome and is consistent with other reports where neoadjuvant chemotherapy facilitated less radical surgery. The patient’s quality of life following organ-preserving surgery has been favorable. At the most recent clinical follow-up, she reported normal daytime urinary continence with no episodes of urgency, incontinence, or dysuria. While a formal validated quality-of-life questionnaire was not administered in this clinical setting, the absence of lower urinary tract symptoms and the return to normal daily activities indicate a good health-related quality of life in the early postoperative period, underscoring a key benefit of the preservation strategy. Long-term follow-up will be essential to fully assess functional outcomes.

Table 1.

Primary ES/PNET of the urinary bladder: summary of reported cases (n = 40).

Author, year	Age (years)/Sex	Presentation	Tumor size (cm)	Location	Metastasis	Treatment	Outcome
Baisakh et al, 2020[8] (case series)
Case 1	72/M	Renal failure, B/L hydronephrosis	2.9	Left lateral wall	Lung, liver	Radical cystoprostatectomy; palliative chemo; RT; B/L nephrostomy	DOD, 19 months
Case 2	81/M	Dark urine, L hydronephrosis	6.4	Left lateral wall/neck	Lung, liver	Partial cystectomy; palliative chemo; RT; U/L nephrostomy	Died (pulmonary embolism), 7 months
Case 3	4/M	Gross hematuria	3.7	Dome	Liver, abdominal wall	TURBT, partial cystectomy; adjuvant chemo; RT	DOD, 14 months
Case 4	7/M	Gross hematuria	15	Dome, trigone, ureters	None	TURBT, radical cystectomy; palliative chemo; RT; ileal conduit	NED, 5 months
Case 5	15/F	Microscopic hematuria	11	Dome, trigone, bladder neck, ureters	Kidney	TURBT, radical cystectomy; adjuvant chemo; ileal conduit	NED, 9 months
Case 6	18/F	Microscopic hematuria	3.5	Dome	None	TURBT, partial cystectomy; adjuvant chemo	LTF (disease-free at 2 months)
Case 7	21/F	Fever, acute urinary retention	4.4	Dome	None	TURBT, partial cystectomy; adjuvant chemo	DOD, 11 months
Case 8	21/F	Lower abdominal pain, gross hematuria	7	Dome	None	Partial cystectomy; adjuvant chemo	NED, 2 years
Case 9	30/F	Gross hematuria	4.8	Trigone, neck	None	TURBT, radical cystectomy; adjuvant chemo; ileal conduit	NED, 7 months
Case 10	38/M	Fatigue, incontinence, urgency	6	Left lateral wall, dome	None	TURBT, partial cystectomy; adjuvant chemo	DOD, 19 months
Case 11	59/F	Lymphedema of legs	9	Dome, trigone, ureters	None	Radical cystectomy; adjuvant chemo; ileal conduit	LTF (disease-free at 11 months)
Case 12	61/M	Microscopic hematuria	14	Dome, trigone, neck, ureters	None	TURBT, radical cystectomy; adjuvant chemo; ileal conduit	NED, 2 years
Case 13	62/M	Fever, lower abdominal pain	8.3	Right lateral wall, dome	None	TURBT, radical cystoscopy; adjuvant chemo; ileal conduit	NED, 18 months
Banerjee et al, 1997[10]	21/M	Microscopic hematuria, dysuria	8 × 6 × 4	Right lateral wall	None	Cystectomy; VAC chemo	NED, 18 months
Gousse et al, 1997[11]	15/F	Gross hematuria	3 × 2 × 2	Right lateral wall	None	TURBT + partial cystectomy; VDC/IE chemo	NED, 18 months
Desai, 1998[12]	38/F	Gross hematuria	12 × 7 × 3.5	Posterior, bilateral	None	Radical cystectomy + TH/BSO	Unknown
Mentzel et al, 1998[13]	62/M	Dark urine, fever, backache, AUR	14 × 10 × 10	Unspecified	Rectal, retroperitoneal, pulmonary	TURBT + nephrostomy; no chemo	DOD, 3 weeks
Colecchia et al, 2002[14]	61/F	Hydronephrosis, renal failure	Unspecified	Unspecified	Pulmonary	None	Unknown
Kruger et al, 2003[15]	81/M	Lymphedema, fatigue, incontinence	Unspecified	Unspecified	Pelvic, retroperitoneal	TURBT + nephrostomy; no chemo	DOD, 2 weeks
Ellinger et al, 2006[16]	72/M	Hematuria, oliguria	Unspecified	Unspecified	Abdominal wall	TURBT; metastasis resection	Poor condition, 2 months
Lopez-Beltran et al, 2006[4]	21/F	Frequency, dysuria, gross hematuria	9 × 8 × 6	Posterior, bilateral	None	Radical cystectomy + TH/BSO; chemo + imatinib	NED, 36 months
Osone et al, 2007[17]	10/M	Dysuria, hematuria	1	Base	None	TURBT; modified P6 chemo	NED, 24 months
Al Meshaan et al, 2009[18]	67/F	Hematuria, fever	3 × 2.5 × 1	Posterior wall	Pelvic LN, pulmonary	TURBT + partial cystectomy	DOD, 8 months
Rao et al, 2011[19]	14/F	Abdominal lump, pain	15 × 12 × 7.5	Posterior wall	None	Sleeve resection; chemo after recurrence	Relapse, 6 months
Busato et al, 2011[20]	57/F	Pelvic pain, dysuria, hematuria	3.3 × 1.5 × 2.2	Right base	None	TURBT; VDC/IE chemo	NED, 27 months
Okada et al, 2011[21]	65/M	Gross hematuria, dysuria	5	Left posterior wall	None	TURBT + cystectomy; VIDE chemo + RT	DOD (mesenteric thrombosis), 22 months
Zheng et al, 2011[9]	74/M	Frequency, dysuria, hematuria	Unspecified	Neck	Pelvic LN	Palliative TURBT; modified VAC chemo	DOD, 4 months
Sueyoshi et al, 2014[22]	10/M	Polyuria, abdominal swelling	13.5 × 13.1 × 12.9	Right lateral wall	None	Partial cystectomy; neoadjuvant/adjuvant VDC/IE chemo	NED, 11 months
Vallonthaiel et al, 2016[23]	27/F	Frequency, hematuria	10.3 × 9.8 × 4.7	Left anterior/lateral	Pelvic LN	TURBT; VAC chemo	NED, ≥ 3 months
Lam et al, 2016[24]	30/F	Polyuria, gross hematuria	6.4 × 9.4 × 7.7	Right lateral wall	None	TURBT + cystectomy + Indiana pouch; VAC/IE chemo	NED, 12 months
Tonyali et al, 2016[2]	38/F	Gross hematuria	4 × 2.6 × 2.5	Right lateral wall	None	Radical cystectomy + LND + TH/BSO + ileal conduit; VDC/IE chemo	NED, 14 months
Liu et al, 2020[25]	64/M	Abdominal dull pain	6 × 5	Left lateral wall	None	Unspecified	Unspecified
Gao et al, 2020[26]	45/F	Frequency, urgency, dysuria	3	Right lateral wall, neck	None	TURBT + radical cystectomy + TH + ileal conduit; VAC chemo	NED, 24 months
Zhang et al, 2020[27]	78/F	Gross hematuria, clots, LUTS	6.3 × 4.4	Right posterior wall	None	TURBT	Unspecified
Orbegoso-Celis et al, 2021[28]	Newborn/M	Prenatal mass, postnatal hematuria	2.7 × 2.5	Posterior wall	None	Partial cystectomy; adjuvant chemo	NED, 3 months
Wu et al, 2021[29]	66/M	Gross hematuria	3.7 × 2.5	Anterior wall	None	Partial cystectomy; EP chemo + RT → recurrence → TURBT + RT → metastasis → PCN	DOD, 12 months
Howe et al, 2021[30]	45Day /F	Gross hematuria	1.2	Posterior wall	None	Neoadjuvant CT; TURBT, partial Cystectomy	NED, 18 months
Tan et al, 2023[31]	19/F	Gross hematuria	5.5 × 3.6	Left posterior wall	None	TURBT; gemcitabine chemo	NED, 24 months
Mao et al, 2024[32]	19/M	Gross hematuria	4.5 × 4.5 × 3	Left wall	None	Radical cystectomy along with bilateral ureterocutaneostomy + + adjuvant chemo	NED, 12 months
Present case	15/F	Gross hematuria, Lower abdominal pain, irritative voiding	9 × 8.5 × 6.5	Dome	None	Neoadjuvant VDC/IE chemo + Partial cystectomy + Adjuvant VDC/IE chemo + RT	NED, 2 months

AUR, acute urinary retention; B/L, bilateral; U/L, unilateral; DOD, died of disease; LND, lymph node dissection; LTF, lost to follow-up; LUTS, lower urinary tract symptoms; NED, no evidence of disease; PCN, percutaneous nephrostomy; RT, radiotherapy; TH/BSO, total hysterectomy/bilateral salpingo-oophorectomy; TURBT, transurethral resection of bladder tumor.

Chemotherapy regimens: VAC, vincristine, actinomycin-D, cyclophosphamide; VDC, vincristine, doxorubicin, cyclophosphamide; IE, ifosfamide, etoposide; VIDE, vincristine, ifosfamide, doxorubicin, etoposide; EP, etoposide, cisplatin; P6, cyclophosphamide/pirarubicin/vincristine followed by ifosfamide/etoposide.

Conclusion

This case report supports the use of neoadjuvant chemotherapy and bladder-preserving surgery in pediatric and adolescent patients with primary bladder ES/PNET. The achievement of a pCR following neoadjuvant chemotherapy highlights the potential to mitigate the long-term morbidity of radical surgery without compromising oncological outcomes in carefully selected patients. Future efforts should focus on integrating molecular diagnostics to better predict chemosensitivity and optimize patient selection for bladder-preserving strategies.

Ethical approval

Ethical approval was obtained from ethical review committee of Damascus University.

Consent

Written informed consent was obtained from the patient’s parents/legal guardian for publication and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Sources of funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

M.A.A.H.: Conceptualization, Writing – Original Draft, Data Curation, Visualization. N.A.: Performed and supervised the operation, Review & Editing, Resources. K.G.: Resources, Investigation, Writing – Review & Editing, Formal analysis. All authors read and approved the final version of the manuscript.

Conflicts of interest disclosure

None.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Murad Ahmad Al Hasan.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.