Stesura Seveso Archivio Italiano di Urologia e Andrologia 2023; 95(3):11533 1 ORIGINAL PAPER INTRODUCTION Although uncommon, primary sarcoma of the urinary bladder (SUB) is an aggressive type of bladder cancer (BCa), accounting for less than 1% of all BCa. The most common risk factors for the development of this disease is smoking and previous exposure to radiotherapy (RT) and cyclophosphamide (1, 2). Based on mesenchymal and epithelial components, SUB can be classified as Sarcomatoid carcinoma (SC) and Carcinosarcoma (CS), both considered malignant biphasic tumors (MBT) by the World Health Organization having malignant epithelial and mesenchymal elements (3). More recently researchers have cast doubts on the significance of distinguishing between these two entities in both bladder and other solid malignancy as they consider these two his- tological subtypes as separate moments between epithelial (Sarcomatoid carcinoma) and mesenchymal differentiation (Carcinosarcoma) (4). Usually, the epithelial element con- tains high-grade transitional-cell carcinoma with some epi- dermoid and/or glandular differentiation, while the heterol- ogous element contains chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, leiomyosarcoma, fibrosarcoma, or rhabdomyosarcoma. Both SC and CS cases are most common among older men, manifesting as fast- growing, advanced-stage polypoid tumors (1-4). When the mesenchymal element lacks epithelial components, SUB can be considered a true heterologous sarcoma (TS). Usually, treatment of SUB has been deduced from the management of urothelial carcinoma (UC) of the bladder. Muscle-invasive UC of the bladder often results in distant metastasis after radical cystectomy, and therefore, neo- adjuvant or adjuvant chemotherapy has been recom- mended as a part of a multimodal approach (5, 6). However, because of to the rarity of SUB and the absence of randomized controlled trial in this setting, definitive conclusions about the optimal treatment option cannot be made. Poor outcomes have been reported in patients with SUB, whatever the treatment used. Even after adjust- Purpose or Objective: Primary sarcoma of the urinary bladder (SUB) is a rare but aggressive form of bladder cancer (BCa). Available evidence on SUB is limited to case reports and small series. The aim of the present multi-institutional study was to assess the clinical fea- tures, treatments, and outcomes of patients with SUB. Materials and methods: Using a standardized database, 7 insti- tutions retrospectively collected the demographics, risk factors, clinical presentation, treatment modalities and follow-up data on patients with SUB between January 1994 and September 2021. The main inclusion criteria included BCa with soft tissue tumor histology and sarcomatoid differentiation. Results: Fifty-three patients (38 men and 15 women) were iden- tified. Median follow-up was 18 months (range 1-263 months). Median age at presentation was 69 years (range 16-89 years). Twenty-six percent of patients had a prior history of pelvic radiotherapy (RT), and 37% were previous smokers. The main presenting symptoms at diagnosis were hematuria (52%), pelvic pain (27%), and both hematuria and pelvic pain (10%). American Joint Committee on Cancer (AJCC) 8 th edition stage II, III and IV at diagnosis were 21%, 63% and 16%, respectively. Treatment modalities included surgery alone (45%), surgery plus neo- or adjuvant-chemotherapy (17%), surgery plus neo- or adjuvant-RT (11%), RT with concurrent chemotherapy (4%), neo-adjuvant chemotherapy plus surgery plus adjuvant RT (2%) and palliative treatment (21%). Rates of local and distant recur- rences were 49% and 37%, respectively. Five-year overall sur- vival and progression-free survival (PFS) were 66.5% and 37.6%, respectively. No statistically significant differences in PFS between the treatment modalities were observed. Conclusions: Primary SUB is a heterogeneous disease group, commonly presenting at advanced stages and exhibiting aggres- sive disease evolution. In contrast to urothelial carcinoma, the primary pattern of recurrence of SUB is local, suggesting the need for multimodal approaches. Continuous international col- laborative efforts seem warranted to provide guidance on how to best tailor treatments based on SUB-specific indices. KEY WORDS: Primary sarcoma of the urinary bladder (SUB); Bladder cancer. Submitted 19 June 2023; Accepted 1 July 2023 Primary Bladder Sarcoma: A multi-institutional experience from the Rare Cancer Network Piero Bettoli 1, 2, ZhihuiAmy Liu 3, Natalia Jara 4, Federico Bakal 1, William Wong 5, Mario Terlizzi 6, Paul Sargos 6, Thomas Zilli 7, Juliette Thariat 8, Sebastian Sole 4, 9, Guillaume Ploussard 10, Sharad Goyal 11, Peter Chung 3, Alejandro Berlin 3, Claudio V. Sole 4, 9 1 Department of Radiation Oncology, Fundación Arturo López Pérez, Santiago, Chile; 2 Facultad de Medicina, Universidad de Los Andes, Santiago, Chile; 3 Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada; 4 Department of Radiation Oncology, Instituto de Radiomedicina, Santiago, Chile; 5 Department of Radiation Oncology, Mayo Clinic Arizona, Phoenix, USA; 6 Department of Radiation Oncology, Institute Bergonie, Bordeaux, France; 7 Department of Radiation Oncology, Geneva University Hospital, Geneva, Switzerland; 8 Department of Radiation Therapy, Centre Francoise Baclese, Caen, France; 9 Facultad de Medicina, Universidad Diego Portales, Santiago, Chile; 10 Department of Urology, La Croix du Sud Hospital, Toulouse, France; 11 Department of Radiation Oncology, George Washington University Hospital, Washington DC, USA. DOI: 10.4081/aiua.2023.11533 Summary Archivio Italiano di Urologia e Andrologia 2023; 95(3):11533 P. Bettoli, Z. Liu, N. Jara, et al. 2 ing for tumor stage, overall survival (OS) rates for SUB vs high-grade, pure UC are 54% vs 77% at 1 year and 37% vs 47% at 5 years, respectively (4, 7). Published data on SUB only consist of case reports and limited case series. Not much is understood of SUB biol- ogy and behavior and its rarity does not permit to design specific treatment guidelines. Thus, we intend to summa- rize the current multi-institutional knowledge of SUB and present an overview of the epidemiology, clinical features, and management of this uncommon type of BCa that can help clinicians to better tailor clinical decisions on this rare disease. METHODS Data on SUB from January 1994 to September 2021 from 7 institutions were retrospectively collected. International Review Board (IRB) approval based on each country/insti- tution was obtained for retrospective review of data. We only collected data from localized primary bladder tumors with soft tissue tumor histology, including SC, CS and TS. The data obtained included age, gender, country and institution, symptoms at the time of diagnosis, risk factors (smoking and RT exposure), tumor size, tumor location, margins and nodal status. Sarcoma subtype, grade and specific immuno-histochemical markers of these tumors were noted. Staging at the time of patholog- ical diagnosis was based on the TNM (tumor, lymph node, metastasis) classification for genitourinary tumors. Treatment modalities analyzed included cystectomy (rad- ical, partial, other), RT (definitive, adjuvant, neo-adjuvant or palliative) and chemotherapy (neo-adjuvant, adjuvant, radio-sensitizer or palliative). Overall survival (OS), cancer-specific survival (CSS), dis- ease-free survival (DFS), distant metastases (DM) and local control (LC) were calculated from diagnosis to the date of any specific event or the date of last follow-up in case an event did not occur. Probabilities for OS, CSS and DFS were determined by Kaplan-Meier estimates. Local recurrence (LR) and DM were estimated using cumulative incidence function con- sidering death as a competing risk. Selective comparisons of survival curves were calculated by the log-rank test. Multivariate models were not used because of the small number of patients and events. For statistical analyses the software program STATA (version 13; College Station, Texas, USA) was used. RESULTS Fifty-three patients were evaluated, 38 men (72%) and 15 women (28%), who had a median age at presentation of 69 years (range 16-89 years). Twenty-six percent of patients had a prior history of pelvic RT; contrary to patients with transitional cell carcinoma, only 37% of patients had a history of tobacco use. Symptoms at diag- nosis were mainly hematuria (52%), pelvic pain (27%), and both hematuria and pelvic pain (10%). Median tumor size was 4.5 cm (range 1.5-9.5 cm). Extra- vesical spread (T3/T4) was the most common presenta- tion of the primary tumor in 59% of cases. Nodal metas- tases were identified in 35% of patients. AJCC 8th edition stage II, III and IV at diagnosis were 21%, 63% and 16%, respectively. The majority of tumors presented with high grade histology (88%). Distribution of TS and MBT were 43% and 57%, respectively. Leiomyosarcoma was the most common histology in the TS group (63%), followed by angiosarcoma (13%), pleomorphic undifferentiated sarcoma (10%), rhabdomyosarcoma (7%), chondrosarco- ma of soft tissue (3%) and leiomyoma (3%). Table 1 pres- ents patient and tumor characteristics. Seventy-three percent of patients underwent radical or par- tial cystectomy. Specifically, treatment modalities included surgery alone (45%), surgery preceded or followed by either chemotherapy (17%) or radiotherapy (11%), defini- tive radiotherapy with concurrent chemotherapy (4%), neo-adjuvant chemotherapy plus surgery plus adjuvant radiotherapy (2%) and palliative treatment (21%). Treatment modalities are outlined in Table 2. Table 1. Patient and tumor characteristics. Patients characteristics N (%) Age mean 69 Gender Male 38 (72) Female 15 (28) Prior history of RT 14 (26) Tobacco exposure 20 (37) Symptoms Hematuria 28 (52) Pelvic pain 14 (27) Both 5 (10) Other 6 (11) Tumor size (median) 4.5 cm (1.5 -9.5) T stage T1/T2 22 (41) T3/T4 31 (59) Nodal metastases 19 (35) AJCC II 11 (21) III 33 (63) IV 9 (16) Malignant Biphasic Tumors (MBT) 23 (43) True Sarcoma (TS) 31 (57) Leiomyosarcoma 19 (61) Angiosarcoma 7 (22) Pleomorphic undifferentiated sarcoma 2 (7) Rhabdomyosarcoma 2 (7) Chondrosarcoma 1 (3) Table 2. Treatment modalities. Treatment modalities N (%) Surgery alone 24 (45) Surgery plus neo-adjuvant or adjuvant chemotherapy 9 (17) Surgery plus neo-adjuvant or adjuvant radiotherapy 6 (11) Definitive radiotherapy with concurrent chemotherapy 2 (4) Neo-adjuvant chemotherapy plus surgery plus adjuvant radiotherapy 1 (2) Palliative 11 (21) Archivio Italiano di Urologia e Andrologia 2023; 95(3):11533 3 Primary bladder sarcoma Median follow-up was 18 months (range 1-263 months). Local recurrence (LR) occurred in 49% of patients and dis- tant metastases (DM) were present in 37%. Five-year OS and PFS were 66.5% and 37.6%, respectively. Kaplan- Meier curves for OS and PFS and the cumulative inci- dence for LR and DM are shown in Figures 1, 2, 3 and 4 respectively. When outcomes in subgroups were examined, a more advanced tumor stage (T2 vs T3/T4) correlated to shorter PFS (median PFS for T2-category was not reached and for T3/T4 was 8.4 months; p = 0.059). Prior history of pelvic radiotherapy also related to lower PFS (7 vs 31 months, p = 0.0018) and OS (9 vs 43 months, p = 0.0007). We found no statistically significant differences in PFS between treatment modalities or between the presence vs absence of epithelial components (TS and MBT). DISCUSSION Although the occurrence of rare cancers in the general public is a serious health issue as a whole, acquiring sta- tistically-reliable clinical trial data is difficult due to the low number of patients with an individual rare cancer type within specific areas (8). Since most available literature on rare cancers is pub- lished as single-institution case reports, it is arduous to draw prognostic implications from these data; further- more the impact of local practices on treatment outcomes is amplified when dealing with rare diseases. Patients with rare neoplasm show significantly poorer results than patients with more common malignancies; mean 5-year survival for the former is up to 20% lower than for the lat- ter (9). This is the case with primary SUB, a disease com- prising less than 1% of all BCa, which poses a challenge in the treatment of this uncommon histological variant. Poor outcomes have been reported in patients with SUB, whatever the treatment used. The five-year overall survival (OS) rate of the present cohort is 66.5%, which exceeds the findings of previous studies where survival rates at five years were consistently below 50% (4, 10, 11). This difference in outcomes can be attributed, at least partial- ly, to two key factors within the study. Firstly, this cohort predominantly consisted of a younger population, with a median age at presentation of 69 years, which is lower than other reports (4). Younger patients have generally been associated with better treatment tolerance, higher overall fitness levels, and potentially more favorable dis- ease characteristics, all of which could contribute to improved survival rates. Secondly, the analysis encom- passed both malignant biphasic tumors (CS and SC) and true heterologous sarcomas (TS). By including both types of tumors, we accounted for the inherent biological diver- Figure 1. OS 5-year rate 66.5% (53.3-83) Figure 2. PFS 5-year rate: 37.6% (25.8-54.7). Figure 3. LR 5-year rate: 49% (34-64). Figure 4. DM 5-year rate: 36.9% (21.4-52.4). Archivio Italiano di Urologia e Andrologia 2023; 95(3):11533 P. Bettoli, Z. Liu, N. Jara, et al. 4 sity, variable clinical behavior of both entities and perhaps different outcomes. Twenty-six percent of the patients of the cohort have a pre- vious history of pelvic radiation therapy (RT), observing inferior outcomes in this subgroup compared to those with- out prior RT (median OS of 9 vs. 43 months, p = 0.0007). Is well known that Radiation-induced sarcomas pose treat- ment challenges as they arise in areas with complications from previous treatments, making surgical removal diffi- cult. Retrospective analyses have shown poor prognosis in these patients compared to sporadic soft-tissue sarcomas, with 5-year OS rates ranging between 32% and 45% (12) which are in line with the findings of this study. Continuing with subgroup analyses, patients with extra- vesical spread (T3/T4) exhibit notable decreases in pro- gression-free survival (PFS) compare to those with less advanced tumors (median PFS for T2-category was not reached and for T3/T4 was 8.4 months). The reduced PFS observed in this particular subgroup of patients (T3/T4) can be attributed to the higher likelihood of developing distant metastases, but also because of the complex rela- tionship between advanced tumor stage and critical anatomical structures, resulting in a potentially decreased effectiveness of local treatment. Data from pelvic sarco- mas exemplify this last phenomenon, with successful attainment of a microscopically margin-negative resection (R0) surgery achieved only in 70% of cases (13). Contrary to UC, where distant recurrence is the primary pattern, this study reveals that rates of local and distant recurrences observed were 49% and 37%, respectively. These findings hold significant implications, particularly considering that approximately 60% of patients in this cohort exhibit extra-vesical spread (T3/T4). The high rates of local failures observed emphasize the critical need for optimizing local therapies, particularly within the lat- ter sub-group. Typically, the treatment approach for SUB has been extrapolated from the management of UC of the bladder, where cystectomy and chemotherapy are considered fun- damental in a multimodality approach (5, 6). Retroperitoneal sarcomas (RPS) exhibit a behavioral pat- tern that aligns more closely with the presents findings, showing a higher incidence of local recurrence, which remains the primary cause of mortality (14). Within this context, local recurrence and metastatic disease occur in approximately 50-60% and 20% of cases, respectively (15), mirroring the failure pattern observed in this study. The importance of local control drives management of RPS, with surgery been the mainstay of curative intent therapy (16). Complete gross resection (R0 or R1) has been associated with improved disease-free survival (17). However, even with a histologically negative margin (R0), local recurrence can still occur (18). Considering the high incidence of local recurrences following surgery, neoadju- vant radiotherapy has emerged as an attractive yet con- troversial option for RPS (19, 20). Despite the retrospective nature of this study, and there- fore hampered by its intrinsic biases, the high local failure rates seen in this cohort prompts the hypothesis that neoadjuvant radiotherapy as part of a multi-disciplinary approach for SUB may play an important role in reducing loco-regional failure rate and improving, at least to some extent, the survival of this patients, especially in higher tumor stages (T3/T4) where R0 surgery with wide mar- gins is more difficult to obtain and were poorer outcomes we have observed. Although the existing evidence is limited, our retrospective data can provide valuable insights into this uncommon neoplasm, enabling clinicians to make more informed clin- ical decisions tailored to this rare disease. CONCLUSIONS Primary SUB is a heterogeneous disease group, common- ly presenting at advanced stages and exhibiting aggressive disease evolution. In contrast to UC, the primary pattern of recurrence of SUB is local, suggesting the need for mul- timodal approaches. Continuous international collabora- tive efforts seem warranted to provide guidance on how to best tailor treatments based on SUB-specific indices. REFERENCES 1. Lopez-Beltran A, Pacelli A, Rothenberg HJ. Carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological study of 41 cases. J Urol. 1998; 159:1497-1503. 2. Mukhopadhyay S, Shrimpton AE, Jones LA. Carcinosarcoma of the urinary bladder following cyclophosphamide therapy: evidence for monoclonal origin and chromosome 9p allelic loss. Arch Pathol Lab Med. 2004; 128:e8-e11. 3. Wick MR, Swanson PE. Carcinosarcomas: current perspectives and an historical review of nosological concepts. Semin Diagn Pathol. 1993; 10:118. 4. Wright JL, Black PC, Brown GA, et al. 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Preoperative radiation ther- apy combined with radical surgical resection is associated with a lower rate of local recurrence when treating unifocal, primary retroperitoneal liposarcoma. J Surg Oncol. 2016; 114:814-20. 20. Bonvalot S, Gronchi A, Le Pechoux C, et al. Preoperative radio- therapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2020; 21:1366-77. CONFERENCE PRESENTATION Bettoli P, Liu ZA, Jara N, et al. Primary Bladder Sarcoma: a multi-institutional experience from the Rare Cancer Network Presentation Number: PO-1219: European Society for Radiotherapy and Oncology (ESTRO) congress; July 31 - 9Facultad de Medicina, Universidad Diego Portales, Santiago, Chile. August 04, 2020; Vienna, Austria. Correspondence Piero Bettoli, MD (Corresponding Author) piero.bettoli@falp.org postal address 7591067 Federico Bakal, MD federico.bakal@falp.org Fundación Arturo López Pérez, Santiago, Chile ZhihuiAmy Liu, MD ZhihuiAmy.liu@uhn.ca Peter Chung, MD Peter.Chung@rmp.uhn.ca Alejandro Berlin, MD Alejandro.Berlin@rmp.uhn.ca Princess Margaret Hospital, Radiation Oncology, Toronto, Canada Natalia Jara, MD njarao@gmail.com Sebastian Sole, MD sebasole@gmail.com Claudio Sole, MD claudio.solep@iram.cl Clinica Instituto de Radiomedicina (IRAM), Santiago, Chile Facultad de Medicina, Universidad Diego Portales, Santiago, Chile William Wong, MD wong.william@mayo.edu Mayo Clinic Arizona, Radiation Oncology, Phoenix, USA Mario Terlizzi, MD terlizzimario@yahoo.fr Paul Sargos, MD P.Sargos@bordeaux.unicancer.fr Institute Bergonie, Radiation Oncology, Bordeaux, France Thomas Zilli, MD Thomas.Zilli@hcuge.ch Hospitaux Universiaires de Geneve, Radiation Oncology, Geneve, Switzerland Juliette Thariat, MD jthariat@gmail.com Centre Francoise Baclese, Radiation Oncology, Caen, France Guilaume Ploussard, MD g.ploussard@gmail.com La Croix du Sud Hospital, Urology Department, Quint Fonsergrives, France Sharad Goyal, MD shgoyal@mfa.gwu.edu George Washington University Hospital, Radiation Oncology, Washington DC, USA Conflict of interest: The authors declare no potential conflict of interest.