Advances and Challenges in the Multidisciplinary Treatment of Retroperitoneal Infantile Fibrosarcoma in Early Life.

Three RIFS patients were identified during the study period. A summary of the clinical characteristics and treatment details is presented in Table  1 . Details the characteristics of the included RIFS patients. Abbreviations: CHT: chemotherapy, IVC: inferior vena cava, LIV: left iliac veins, LRV: left renal vein, PTFE: polytetrafluoroethylene, RIFS: retroperitoneal infantile fibrosarcoma, RIV: right iliac veins, TNM: Tumor Node Metastasis oncologic staging system, US: ultrasound. A male infant was delivered vaginally at 39 weeks of gestation, weighing 3600 g. The newborn had a normal perinatal period. At 6 months of age he presented with vomiting, constipation, and weight loss. An ultrasound (US) was performed with the identification of an abdominal mass. CT, MRI, and angiography confirmed a large retroperitoneal mass (60 × 75 × 80 mm), with encasement/infiltration of the IVC, which appeared thrombosed from the confluence of the iliac veins to the infrahepatic IVC (Figure  1A ). The abdominal aorta was displaced anteriorly but patent. (A) Case 1: Arteriography: RIFS (*) involving IVC and the confluence of the LIV and RIV. (B) Case 1: Intraoperative image: infrarenal IVC is removed en‐bloc with RIFS and replaced by a PTFE graft Y‐shaped conduit (C) connecting the proximal IVC to the origin of the LIV and RIV. (C) Case 2: preoperative abdominal CT scan: RIFS (*) involving the IVC and right renal vein. The yellow arrow shows the large collateral venous drainage. (D) CASE 2: postoperative abdominal CT scan: Ligated IVC (red arrow). Blood from the iliac veins drains through the large collateral (yellow arrow) in the lumbar veins. IVC: inferior vena cava, LIV: left iliac veins, PTFE: polytetrafluoroethylene, RIFS: retroperitoneal infantile fibrosarcoma, RIV: right iliac veins. After biopsy of the mass and subsequent histopathological diagnosis of RIFS, the patient was treated according to the EpSSG 2005 Non‐Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS) protocol and was classified as IRS Group III due to unresectable disease at diagnosis. Neoadjuvant chemotherapy was initiated using the ifosfamide–doxorubicin (IFO–DOXO) regimen, with three planned cycles administered every 21 days and doses adjusted for age and body weight. Each cycle consisted of ifosfamide 100 mg/kg/day for three consecutive days and doxorubicin 2 mg/kg per cycle. After the second cycle, signs of cardiac toxicity were observed, leading to postponement of the third cycle and omission of doxorubicin. Radiological reassessment demonstrated a partial response, with a tumor size reduction greater than 60%. Imaging confirmed infiltration of the infrarenal IVC extended to the bifurcation of the common iliac veins without significant collateral veins. In view of the response to chemotherapy and concerns regarding cumulative chemotherapy‐related toxicity, surgical resection was pursued. The resection of the primary tumor was performed at 8 months of age. Involvement of infrarenal IVC and iliac bifurcation, in the absence of significant collateral vessels, was confirmed intraoperatively; the infrarenal segment of the IVC and a portion of the common right and left iliac veins were removed en‐bloc with the tumor. Two Polytetrafluoroethylene (PTFE) grafts, measuring 7 and 4 mm, were connected in a Y‐shaped configuration to replace the bifurcation of the IVC and its infrarenal portion (Figure  1B ). The immediate postoperative period was unremarkable. The infant was discharged on Day‐14 post surgery. Histopathological examination demonstrated a post‐chemotherapy malignant mesenchymal neoplasm with morphological features consistent with fibrosarcoma. The tumor showed extensive therapy‐related regressive (involutional) changes and an infiltrative growth pattern, with direct involvement of the wall of large venous vessels. Both grafts gradually and progressively occluded within the first 2 months after surgery. A progressive development of venous collaterals allowed an adequate blood return from the legs without any clinical manifestations. The patient is now aged 13 years old, alive and well. A female neonate was transferred to our Institution on Day 3 of life due to a palpable abdominal mass observed at birth. The patient was delivered vaginally at 40 weeks of gestational age, with a birth weight of 2850 g. The perinatal period was otherwise unremarkable. Upon admission, initial laboratory tests were performed according to the institutional protocol for the diagnosis of abdominal masses—including urinary vanillylmandelic acid, serum carcinoembryonic antigen, alpha‐fetoprotein, beta‐human chorionic gonadotropin, and chromogranin A. All the tests resulted in the physiologic range. US and CT revealed a well‐defined retroperitoneal mass measuring approximately 53 × 45 × 60 mm (Figure  1C ). The lesion displaced the right kidney with encasement of the infrarenal IVC. At 25 days of age, the newborn underwent a surgical biopsy that confirmed the diagnosis of RIFS. Given the non‐feasibility of upfront surgery, the patient was treated according to the EpSSG 2005 Rhabdomyosarcoma (RMS) protocol (Low‐Risk Group), with doses adjusted for age and body weight. Neoadjuvant chemotherapy consisted of three cycles of vincristine and actinomycin D (VA), with vincristine administered at 0.05 mg/kg per dose once weekly and actinomycin D at 0.02 mg/kg per dose every 3 weeks. Treatment was well tolerated, with no significant chemotherapy‐related toxicities observed. Radiological evaluation after three cycles showed a very good response, with a tumor reduction greater than 90%. In particular, the infrarenal IVC was completely encased by the tumor, but lumbar veins showed significant compensatory flow (Figure  1C ). Surgical resection was subsequently performed in accordance with the EpSSG 2005 RMS protocol. At 5 months of age, the infant underwent an exploratory laparotomy that revealed a lesion encasing the infrarenal IVC The resection of the mass, together with the right kidney and right adrenal gland, was complicated by a massive bleeding and the need to remove the infrarenal IVC en‐bloc with the tumor. Venous return from the iliac veins and the distal IVC was ensured by a large, preexisting collateral draining into the contralateral lumbar veins (Figure  1D ). No complications occurred, and the patient was discharged on the 13th postoperative day. Final histological analysis revealed a post‐chemotherapy fibrosarcoma with minimal residual viable tumor and prominent therapy‐induced involutional changes. The neoplasm involved the renal hilum, with encasement of hilar structures and diffuse vascular involvement, including obliteration and thrombosis of hilar vessels. The patient, who is currently 15 years old, continues to receive follow‐up surveillance. At present, the patient is alive and well, with no tumor recurrence or significant sequelae, except for a pelvic varicocele. A female infant was prenatally diagnosed with a retroperitoneal mass (Figure  2A ). The patient was born at 38 weeks, weighing 3080 g via spontaneous vaginal delivery with good adaptation to extrauterine life. The perinatal period was unremarkable, and the newborn was asymptomatic. Case 3: Imaging of RIFS at different stages of patient's management: prenatal (A), neonatal (B), intraoperative (C, D, E), and follow‐up (F). (A) Fetal MRI at 32‐weeks of gestation, showing a retroperitoneal mass (green dots) encasing the major vessels (green arrow pointing to the IVC). (B) RIFS (*) encasing the IVC and the origin of both renal veins. (C–E) Arteriography and percutaneous embolization: (C) multiple arterial collaterals feeding the RIFS, (D) yellow arrow: main arterial collateral, (E) embolization of the main collateral (coil is visible in the yellow circle). (F) Abdominal TC‐scan 5 months after embolization of the main arterial branch and Vemurafenib treatment, showing significant reduction of the RIFS. IVC: inferior vena cava; RIFS: retroperitoneal infantile fibrosarcoma. At birth the neonate underwent US, and abdominal CT confirmed a hyper vascular retroperitoneal mass (50 × 43 × 27 mm) displacing the right kidney and encasing the IVC, extending from the upper renal pole to the pelvis, displacing bowel loops anteriorly and infiltrating the mesenteric root (Figure  2B ). At Day‐6 of life, she underwent an open surgical biopsy. The histopathological exam confirmed the diagnosis of RIFS, with the ETV6::NTRK3 gene fusion. Molecular analysis identified a BRAF V600E mutation. Clinically, the infant rapidly showed signs consistent with a right‐sided heart failure due to volume overload: secondary to large intralesional arterio‐venous shunts. She underwent a percutaneous arterial embolization targeting a large lumbar branch supplying the RIFS with rapid and consistent clinical improvement (Figure  2C–E ). Once clinically stable and given the presence of BRAF V600E mutation, targeted therapy with the BRAF inhibitor vemurafenib was initiated at a dose of 10 mg/kg, based on available pediatric evidence supporting its efficacy and tolerability in BRAF‐mutated conditions [ 13 , 14 ]. Treatment response was monitored through regular clinical assessments and serial radiological imaging. At the most recent follow‐up (10 months), a marked (> 80%) tumor reduction was observed on imaging, with no clinically significant treatment‐related toxicities reported. A follow‐up CT scan demonstrated a consistent reduction in the size of the mass (Figure  2F ). Given the substantial and sustained response to medical therapy and the favorable tolerability profile, continuation of long‐term vemurafenib treatment was pursued. Surgical intervention was deferred at this stage, as the potential benefits of resection were carefully weighed against the high risk of postoperative morbidity associated with surgery in this anatomical location.

Study design and conceptualization: Gaia Brunetti, Angelo Zarfati, Giorgio Persano, Giuseppe Maria Milano, and Ida Russo. Formal analysis: Gaia Brunetti, Angelo Zarfati, Giorgio Persano, Giuseppe Maria Milano, and Ida Russo. Funding acquisition: Alessandro Crocoli, Gian Luigi Natali, Rita Alaggio, and Chiara Grimaldi. Investigation: Gaia Brunetti, Angelo Zarfati, Giorgio Persano, Giuseppe Maria Milano, and Ida Russo. Methodology: Gaia Brunetti, Angelo Zarfati, Giorgio Persano, Giuseppe Maria Milano, and Ida Russo. Project administration: Alessandro Crocoli, Gian Luigi Natali, Rita Alaggio, and Chiara Grimaldi. Supervision and validation: Alessandro Crocoli, Gian Luigi Natali, Rita Alaggio, and Chiara Grimaldi. Writing – original draft: Gaia Brunetti, Angelo Zarfati, Giorgio Persano, Giuseppe Maria Milano, and Ida Russo. Writing – review and editing: Alessandro Crocoli, Gian Luigi Natali, Rita Alaggio, and Chiara Grimaldi. Review and approval of the final version: all the authors.

Written informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article. The present study received authorization for publication from the scientific board in the authors' institution.

The authors declare that financial support was received for the research and/or publication of this article. This work was supported also by the Italian Ministry of Health with “Current Research funds”. This study did not receive other types of grants from funding agencies in the public, commercial, or nonprofit sectors.

The study is a retrospective case series. We identified and enrolled all patients diagnosed with RIFS and treated at our pediatric referral center from January 2010 to January 2024. Clinical, biological, radiological, medical, and surgical data were collected and analyzed from medical charts, as well as histological findings and follow‐up outcomes. The inclusion criteria comprised a histological diagnosis of RIFS, pediatric age (under 18 years), and diagnosis and management at our institution during the study period (from January 2010 to January 2024). Patients with no follow‐up or missing data were excluded from the study. This study did not require approval from an ethics committee, as all participants had given informed consent for the anonymized use of their data for research purposes upon hospital admission. The study received authorization for publication from the scientific board in the authors' institution.

RIFS represents a rare subset of malignant mesenchymal tumors and remains the most common soft tissue sarcoma diagnosed in children under 1 year of age [ 2 , 7 ]. Despite its generally favorable prognosis, with reported 5‐year overall survival rates approaching 89%, retroperitoneal involvement, which accounts for roughly 7% of all cases, introduces unique and substantial clinical challenges [ 15 ]. The expansive anatomical nature of the retroperitoneum facilitates silent tumor growth, often leading to delayed symptoms onset and diagnosis. This delay, combined with the complex and intimate relationships between the tumor and critical vascular and visceral structures‐particularly the IVC, creates a therapeutic milieu that is demanding and necessitates nuanced individualized multidisciplinary decision‐making. Overall, the primary therapeutic aim remains the attainment of a complete macroscopic surgical excision with clear margins to reduce the risk of local recurrence [ 8 , 16 ]. However, RIFS frequently involve extensive vascular infiltration, including thrombosis, displacement, or encasement of the IVC and other crucial vital structures, as demonstrated across all the cases in our series. This aggressive anatomical behavior contrasts with the typically low‐grade histology of RIFS and complicates surgical treatment. Indeed, nearly half to two‐thirds of retroperitoneal RIFS cases are deemed unresectable at initial diagnosis due to tumor size, location, or involvement of critical structures, which renders upfront surgery either unsafe or unlikely to achieve complete disease resection [ 8 , 16 ]. Given these challenges, an integrated multidisciplinary approach has become imperative. The treatment paradigm currently encompasses not just surgery but also incorporates neoadjuvant chemotherapy, interventional radiology, and, potentially, targeted molecular therapies to optimize short and long‐term morbidity and outcomes [ 17 ]. This approach seeks a delicate balance: aggressive disease control must be pursued without inflicting undue long‐term morbidity, a consideration of paramount importance in the pediatric population where developmental and functional preservation is critical. The longitudinal nature of this case series‐spanning over a decade‐provides a valuable lens through which observe the evolution of therapeutic strategies for RIFS. It should be acknowledged that the management strategies adopted in this series were influenced by the therapeutic options available at the time of treatment. The earliest cases (Case 1 and 2) were managed over 15 years ago, were managed during a period in which molecularly targeted therapies were not yet available for clinical use. As a result, treatment decisions relied primarily on conventional chemotherapy and surgery, based on the available evidence [ 18 ]. These regimens, while effective in inducing measurable tumor regression, often resulted in only partial responses and significant toxicity, with residual disease deeming challenging surgical options. In this context, the decision to proceed with surgical resection was also informed by concerns regarding the substantial toxicity of standard chemotherapeutic agents in very young children, particularly in patients younger than 12 months. This consideration was especially relevant in Case 2, a neonate, in whom many cytotoxic agents are associated with an unfavorable or unacceptable toxicity profile. Recent advances in molecular characterization have expanded the therapeutic options for selected pediatric tumors, including infantile fibrosarcoma, by enabling the use of targeted therapies directed against specific oncogenic drivers. Most RIFS harbor the characteristic ETV6‐NTRK3 gene fusion; novel agents such as TRK inhibitors (e.g., Larotrectinib) have demonstrated promising activity [ 2 , 5 , 19 , 20 ]. Rarer molecular aberrations such as PRKAR1B‐BRAF fusions, as identified in one of our patients, have extended the options of the therapeutic repertoire to BRAF inhibitors, that have shown efficacy in pediatric diseases characterized by this mutation [ 13 , 14 , 18 ]. The incorporation of targeted agents represents a fundamental advancement in balancing effective disease control with avoidance of treatment sequelae and preservation of patient's quality of life. Emerging evidence from pediatric series suggests that these molecularly targeted approaches can achieve substantial disease control with a favorable safety profile, potentially reducing or delaying the need for extensive surgical procedures. Case 3 represents the more recent clinical scenario, in which advances in molecular diagnostics and the availability of targeted therapies allowed for a different treatment strategy. In this patient, identification of a targetable molecular alteration enabled the use of previously non existing treatment strategies. This approach resulted in over 80% disease reduction while reducing the need for both highly toxic chemotherapy and high‐risk surgical intervention. Taken together, these cases illustrate how therapeutic decision‐making in infantile fibrosarcoma has evolved over time, reflecting both improvements in molecular characterization and the expanding availability of targeted agents. This temporal evolution highlights the importance of individualized, multidisciplinary management and underscores the need to adapt treatment strategies to both patient age, anatomical conditions and the molecular features of the disease. In anatomically complex locations such as the retroperitoneum, where surgical resection may be associated with significant intraoperative and postoperative morbidity, targeted medical therapy may represent a valuable alternative or adjunct within a multidisciplinary treatment strategy. Nevertheless, given the lack of long‐term data, careful patient selection, close monitoring, and individualized decision‐making remain essential. Additionally, the role of interventional radiology has become increasingly prominent within this multidisciplinary framework. When the patient in our series presented with acute, life‐threatening complications attributable to intralesional arteriovenous shunts leading to heart failure, a percutaneous arterial embolization provided a minimally invasive, rapid and effective intervention to stabilize hemodynamics, enabling safer administration of systemic therapies. This highlights how symptom‐directed, supportive interventions have become integral in managing not only tumor burden but also its physiological sequelae. Prenatal diagnosis also played a role in our experience, with one case involving antenatal detection. Early identification via fetal imaging, such as ultrasound or MRI, facilitated preemptive multidisciplinary planning and allowed for timely postnatal evaluation and management. This capability exemplifies how advances in diagnostic technology can improve patient outcomes through early intervention, streamlined care coordination, and possibly even reduced disease burden at presentation [ 21 ]. Despite these advances, the extreme rarity of RIFS continues to limit the availability of standardized treatment protocols. As such, individualized multidisciplinary patient‐centered care remains paramount. Accurate histopathological diagnosis complemented by detailed molecular analyses forms the cornerstone upon which personalized treatment plans are constructed. Sustained interdisciplinary collaboration among pediatric surgeons, oncologists, interventional radiologists, pathologists, and geneticists is essential to navigate the complexities of each case effectively. Furthermore, vigilant, lifelong surveillance is required to monitor for disease recurrence and mitigate long‐term sequelae related to both the tumor and its treatment. Previous reports have suggested that the retroperitoneum may represent a site associated with less favorable outcomes in patients infantile fibrosarcoma. In particular, Gallego et al. reported an aggressive clinical course in retroperitoneal cases, characterized by limited response to chemotherapy and a high risk of local recurrence [ 5 ]. These findings were primarily attributed to delayed diagnosis, larger tumor size at presentation, deep anatomical location, and technical challenges in achieving complete surgical resection, rather than to distinct histopathological characteristics. Notably, the tumors described in that series harbored the canonical ETV6::NTRK3 fusion, yet still demonstrated unfavorable outcomes, suggesting that tumor biology alone may not fully account for the observed prognosis. In comparison, the outcomes observed in our series appear more favorable; however, such comparisons should be interpreted with caution given the limited number of cases and the heterogeneity across published reports. In our cohort, a multidisciplinary approach and, when feasible, complete surgical resection may have contributed to improved local disease control despite the challenging retroperitoneal location. About pathological features, we did not identify consistent histological or molecular characteristics that clearly correlated with recurrence. Instead, factors such as tumor extent, involvement of adjacent vascular and visceral structures, and the feasibility of complete resection may play a more relevant role in influencing recurrence risk. It is also noteworthy that the cases reported by Gallego et al. presented with severe anemia at diagnosis, likely related to hemorrhagic complications secondary to extensive vascular involvement. In contrast, although vascular infiltration was also observed in our series, it was not associated with overt hemorrhage but rather with hemodynamic compromise, including high‐output cardiac failure. In this context, the availability of a multidisciplinary management strategy, including interventional radiology and complex surgical approaches, was essential to achieve symptom control and local disease management. Finally, it should be acknowledged that the small sample size of our series limits the generalizability of these observations and may have led to an underestimation of recurrence risk, despite the relatively long duration of follow‐up. Furthermore, the differing vascular approaches required during surgery warrant consideration. The vascular findings differed between Case 1 and Case 2 and may reflect distinct patterns of tumor–vessel interaction, which were at least partially anticipated on preoperative imaging. Overall, beyond the extent of vascular involvement, the pattern and temporal evolution of tumor–vessel interaction may influence collateral development and surgical strategy [ 8 ]. Careful preoperative imaging assessment of vessel patency, possible wall invasion, and collateral pathways may therefore assist in surgical planning for retroperitoneal infantile fibrosarcoma. Looking forward, there is a pressing need for prospective multicentric studies and registries to systematically capture clinical, pathological, and molecular data. Such collaborative efforts will be crucial in refining outcomes, evaluating the efficacy and safety of emerging targeted agents, optimizing timing and extent of surgical intervention, and ultimately developing evidence‐based consensus guidelines. The progressive integration of minimally invasive techniques, focused interventional treatments, and precision oncology holds promise for minimizing the physical and psychological burden of therapy while sustaining high rates of disease control. Multidisciplinary lifelong long‐term follow‐up extending into adulthood will be critical to better understand the durability of benefits and potential occurrence of late complications of each approach. Early referral to specialized tertiary pediatric oncology centers equipped with comprehensive diagnostic and therapeutic resources remains a cornerstone recommendation, facilitating access to cutting‐edge treatments and multidisciplinary expertise.

This decade‐spanning case series, although limited in number, provides a compelling illustration of how the approach to RIFS has transformed over time. It documents the shift from reliance on conventional CHT and invasive surgery to a sophisticated, individualized, multidisciplinary approaches that incorporates interventional radiology, and targeted molecular therapies when indicated. This evolution reflects broader trends in pediatric oncology, emphasizing personalized, mechanism‐driven treatment strategies that aim both for curative intent and minimization of long‐term morbidity. Our experience reaffirms the vital role of integrated care pathways and ongoing innovation in improving outcomes for children affected by this rare yet challenging malignancy.

Retroperitoneal Infantile Fibrosarcoma (RIFS) is an exceedingly rare variant of low‐grade mesenchymal tumors that typically arises in the first year of life [ 1 ]. RIFS is considered part of the Non‐Rhabdomyosarcoma Soft Tissue Sarcomas group, representing the most common soft tissue sarcoma in newborns and infants [ 2 ]. RIFS is generally characterized by a favorable prognosis compared to its adult counterpart, with low metastatic potential and a high degree of chemosensitivity and response to treatment [ 3 , 4 , 5 ]. Despite these apparently favorable features, patients affected by RIFS may be highly symptomatic at presentation, especially due to mass effect on vascular structures [ 1 ]. Overall and, whenever feasible, complete tumor resection is considered a crucial step of treatment [ 6 , 7 , 8 ]. Neoadjuvant chemotherapy (CHT) may be a helpful option in cases where upfront primary tumor resection is not feasible due to comorbidities, symptoms or anatomical features [ 7 ], while adjuvant CHT is reserved to stage III (macroscopic residual tumor after biopsy only or incomplete surgery) and stage IV (distant metastasis) [ 7 ]. The retroperitoneal location is associated with possible diagnostic delay and increased risk of complications [ 5 ]. Infiltration of the retroperitoneal space and its structures, particularly vessels, including the inferior vena cava (IVC) or abdominal aorta and their major branches, can further complicate the management [ 9 ]. The resection of retroperitoneal masses often requires complex surgical strategies, with a non‐negligible risk of morbidity and potential long‐term sequelae [ 10 ]. Given the surgical risks, there is growing interest in multidisciplinary nonoperative strategies. Recently, the use of target therapy is gaining a place in pediatric oncology, with a specific possible application for RIFS [ 11 , 12 ]. This study aims to illustrate the spectrum and evolution over time of treatment strategies for RIFS, as well as its variability in clinical presentation, treatment approaches, and outcomes. By presenting a series of patients treated across different therapeutic eras, this study also highlights how advances in molecular diagnostics and the availability of targeted therapies may influence clinical decision‐making in the management of this rare and complex disease.

The authors declare no conflicts of interest.