Congenital mesoblastic nephroma: a single-center retrospective study

Introduction

Congenital mesoblastic nephroma (CMN) is a rare renal tumor primarily affecting neonates and young infants, accounting for 3–5% of childhood renal neoplasms (1,2). Histologically, CMN is classified into classic, cellular, and mixed subtypes, with cellular and mixed variants associated with higher risks of recurrence and metastasis.

Molecular studies have identified the ETV6::NTRK3 fusion as a distinctive molecular alteration associated with cellular CMN, functioning as a crucial diagnostic marker for this histologic subtype. In contrast, classic and mixed CMNs more commonly exhibit intragenic rearrangements of EGFR, which include internal tandem duplications and kinase domain duplications (KDDs) (3-5). Moreover, a subset of cellular CMNs lacking ETV6::NTRK3 harbor alternative oncogenic drivers, including NTRK1 or BRAF fusions and other kinase rearrangements, underscoring the molecular heterogeneity of this tumor entity (5-7). Despite surgical resection being the mainstay of treatment, standardized postoperative management for high-risk or recurrent cases remains undefined.

Recent advances in targeted therapy and immunotherapy offer potential treatment options for patients with high-risk molecular alterations, yet, clinical experience in CMN is limited. Comprehensive analysis of clinical presentation, molecular profile, and treatment outcomes is essential to inform evidence-based management strategies.

In this study, we retrospectively analyzed nine CMN patients treated at a single center between 2015 and 2024. In this retrospective case series, we describe the clinical, pathological, and molecular characteristics of a consecutive cohort of CMN patients treated at a single institution. By integrating molecular findings with treatment courses and outcomes, we aim to illustrate the heterogeneity of CMN and highlight unresolved challenges in the management of relapsed or molecularly atypical cases. We present this article in accordance with the STROBE and AME Case Series reporting checklists (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-770/rc).

Methods

Patients

This retrospective study included nine children with CMN who were diagnosed and treated at the Children’s Hospital of Nanjing Medical University between January 2015 and January 2024. Diagnosis was established by histopathology, with molecular testing performed when feasible. Of note, two patients within this cohort (Patient IDs: 1 and 4) have been previously reported as individual case studies due to their unique presentation (8,9). Their data are included in this analysis to ensure a comprehensive evaluation of the entire cohort; however, detailed clinical descriptions unique to those reports are not reiterated here. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Nanjing Medical University (No. 202509033-1) and informed consent was taken from all the patients’ legal guardians.

Data collection

Demographic information (age, sex), clinical presentation, imaging findings [ultrasound and computed tomography (CT)], pathological subtype, molecular alterations, treatment strategies, and therapeutic responses were retrieved from electronic medical records. Follow-up data were obtained through outpatient visits or structured telephone interviews.

Pathology and molecular testing

Tumor specimens were independently reviewed by pediatric pathologists and classified into cellular, classic, or mixed subtypes according to histological criteria. Molecular analyses were performed in selected cases using fluorescence in situ hybridization (FISH) and/or next-generation sequencing (NGS). During the study period, molecular testing was not uniformly performed in all CMN cases. Testing for ETV6::NTRK3 was primarily considered in tumors with cellular or mixed histology, atypical clinical features, or disease relapse, reflecting an evolving institutional practice rather than a predefined protocol.

FISH for ETV6::NTRK3 was conducted using commercially available dual-color break-apart probes. Targeted NGS was performed in selected relapsed or high-risk cases using a hybrid-capture-based panel covering recurrent pediatric solid tumor-associated genes, with DNA- and RNA-based assays applied when available to detect gene fusions and structural rearrangements. The EGFR-KDD was identified as an intragenic duplication spanning exons 1–25 to 18–28 and was confirmed by orthogonal methods.

Treatment

All patients underwent surgical resection with curative intent. Postoperative management was individualized based on molecular subtype and disease course. Treatment decisions for relapsed cases were made through multidisciplinary discussion, taking into account histologic subtype, molecular findings, prior therapies, disease burden, and drug availability, rather than a predefined institutional protocol. Patients with relapse or high-risk molecular features received systemic chemotherapy, most commonly vincristine-actinomycin D-cyclophosphamide (VAC) or ifosfamide-carboplatin-etoposide (ICE). Targeted therapies—including larotrectinib, entrectinib, and afatinib—were administered in selected patients according to molecular findings, either alone or in combination with immune checkpoint inhibitors.

Follow-up and outcome measures

Patients were monitored at regular intervals with clinical evaluations and imaging studies. Overall survival (OS) was defined as the time from diagnosis to death from any cause or last follow-up, and event-free survival (EFS) as the time from diagnosis to relapse, progression, or death. Median follow-up duration was calculated for the entire cohort.

Statistical analysis

Descriptive statistics were used to summarize baseline characteristics and treatment outcomes. Given the small sample size, statistical analyses were limited to descriptive methods. OS and EFS were summarized using the Kaplan-Meier method for visualization purposes only, without formal comparative or inferential analysis. Analyses were performed using SPSS version 26.

Results

Patient characteristics

Nine patients with CMN were included in this study. The median age at diagnosis was 2.5 months (range: newborn to 93 months, see Table 1). Six patients were male and three were female, yielding a male-to-female ratio of 2:1. Abdominal mass was the predominant presentation, detected prenatally or incidentally in 90% of cases. Imaging typically showed cystic-solid renal tumors; several lesions demonstrated heterogeneous enhancement on contrast-enhanced CT, suggestive of a rich vascular supply (Figure 1).

Figure 1 Abdominal CT images of Case 3. (A) Non-contrast CT scan demonstrating a large, well-circumscribed, round-like retroperitoneal mass in the right kidney with heterogeneous density and no visible calcification. (B) Contrast-enhanced CT scan showing heterogeneous enhancement of the mass. CT, computed tomography.

Pathology and molecular features

Histopathological examination revealed five cellular types (Figure 2), two classic types, and two mixed types of CMN (Table 1). In the patient harboring an EGFR-KDD, the tumor was classified as cellular CMN based on characteristic histopathologic features, including high cellularity, intersecting fascicles of spindle cells, elongated nuclei, and increased mitotic activity. The diagnosis was independently rendered by experienced pediatric pathologists. Differential diagnoses, particularly infantile fibrosarcoma, were carefully considered and excluded based on the overall morphologic appearance and immunophenotypic profile. Representative histologic and immunohistochemical features of this case are shown in Figure S1. Molecular testing was performed in seven patients. Three tumors harbored the canonical ETV6::NTRK3 fusion. Among the remaining tested cases, one cellular CMN harbored a TPM3::NTRK1 fusion and one demonstrated an EGFR-KDD, while two cases showed no diagnostic alterations identified by the assays performed. Molecular testing was not performed in two patients (Table 1).

Figure 2 Pathological and immunohistochemical features of Case 3. (A) Gross specimens of the resected tumor showing a well-circumscribed mass with solid cut surface. (B) HE staining demonstrating a spindle cell tumor composed of relatively uniform cells with eosinophilic cytoplasm, frequent mitotic figures, and focal hemorrhage and necrosis (original magnification ×200). (C) Immunohistochemistry showing positive pan-TRK expression in tumor cells (original magnification ×200). HE, hematoxylin and eosin; pan-TRK, pan-tropomyosin receptor kinase.

Treatment and therapeutic outcomes

The treatment and outcomes of all patients are summarized in Table 2. All patients underwent radical nephrectomy with negative surgical margins, achieving a 100% complete resection rate. No preoperative biopsy or intraoperative tumor spill was documented. Patient 1 received systemic chemotherapy after complete tumor resection in the initial surgery due to the consideration of soft tissue sarcoma by pathological consultation from another hospital. The remaining 8 patients did not receive combined systemic chemotherapy after the initial surgical treatment. Two cellular type patients (Patient 1 and 4) relapsed postoperatively. Both received salvage chemotherapy (VAC or ICE), with limited benefit.

In the patient harboring a TPM3::NTRK1 fusion, larotrectinib was selected based on its established activity against NTRK fusion-positive pediatric tumors and its regulatory approval in this context. Despite this molecularly matched approach, the patient experienced rapid disease progression. In contrast, the patient with an EGFR-KDD received sequential targeted therapies reflecting both molecular findings and treatment response. Entrectinib was initially administered due to its reported activity against NTRK and selected EGFR alterations, followed by anlotinib in the setting of progression. Subsequent treatment with afatinib, a second-generation irreversible EGFR tyrosine kinase inhibitor (TKI), was chosen based on prior evidence supporting its activity against EGFR-KDDs. Given continued disease activity, afatinib was combined with programmed cell death protein 1 (PD-1) blockade, resulting in disease stabilization.

Follow-up and survival

At a median follow-up of 36 months (range: 12–115 months), eight patients were alive, and two experienced disease relapse. Kaplan-Meier curves are provided to descriptively illustrate OS and EFS within this cohort (Figure 3). One relapsed patient had poor survival despite targeted therapy, whereas the other remains in stable condition under ongoing combined targeted and immunotherapy.

Figure 3 Kaplan-Meier curves of OS and EFS for the study cohort, presented descriptively without inferential or comparative analysis. EFS, event-free survival; OS, overall survival.

Discussion

In this single-center retrospective study, we summarized the clinical features, molecular characteristics, treatment strategies, and outcomes of nine pediatric patients with CMN. Consistent with prior reports, CMN in our cohort predominantly affected neonates and young infants and was generally associated with favorable outcomes following complete surgical resection (10,11). Notably, postoperative relapse was observed only in cellular CMN cases lacking the canonical ETV6::NTRK3 fusion. Given the very small sample size and incomplete molecular testing across cases, this observation should be interpreted descriptively rather than as evidence of increased relapse risk. No statistical inference regarding prognosis can be drawn from this series. Moreover, although two patients in this cohort have been previously reported as individual case studies, their inclusion here allows for a consolidated analysis within a consecutive institutional series, providing contextual comparison across histologic subtypes and molecular alterations rather than isolated observations.

Previous studies have established CMN as a rare renal tumor of infancy, typically diagnosed within the first year of life, with a slight male predominance and frequent right-sided involvement (1,2). The age and sex distribution of the patients in this study were mostly consistent with previous studies, but it is interesting to note that our Patient 1 had onset at 7 years old and relapsed about half a year after surgery and chemotherapy (9). The pathological morphology was considered cellular, but NGS detection revealed the presence of EGFR-KDD mutation, which is an extremely rare and interesting case report. Previous studies have highlighted that the imaging features of CMN are closely associated with its histological subtypes (12). For instance, a recent retrospective analysis of 10 pediatric CMN patients reported that CT findings typically presented as solid lesions or solid-cystic lesions with variable predominance, with moderately heterogeneous enhancement of the solid components and septations during contrast-enhanced scans (13). Notably, the so-called “double-layer sign” was frequently observed in classic CMN, whereas the “intratumor pelvis sign” was present in approximately 90% of cases, spanning both classic and cellular variants. Our findings are largely consistent with these observations. In our cohort of nine patients, the majority of tumors also demonstrated solid or predominantly solid-cystic morphologies on CT, with heterogeneous enhancement patterns comparable to those described previously.

The ETV6::NTRK3 gene fusion is present in approximately 21.5–29% of CMN cases and is considered a defining molecular hallmark of cellular sub-types (1,14). Patients with this alteration usually have excellent outcomes after surgery. In contrast, cellular sub-types patients lacking this fusion may harbor alternative genetic drivers such as EML4::NTRK1 or EGFR-KDD, which may have been associated with more aggressive disease biology and poor treatment responses (6,7,9,15). Targeted inhibitors such as larotrectinib and entrectinib have shown remarkable efficacy in NTRK fusion-positive solid tumors across age groups, leading to their regulatory approval (16). However, resistance can emerge, often due to secondary mutations in the kinase domain. In our series, a case (Case 4) of cellular CMN carrying TPM3::NTRK1 fusion gene experienced relapse and showed minimal benefit from larotrectinib, ultimately resulting in early mortality (8). Our observation of limited larotrectinib efficacy in this patient suggests that resistance mechanisms may differ in this tumor type and highlights the need for alternative strategies, such as next-generation tropomyosin receptor kinase (TRK) inhibitors or rational drug combinations.

Of particular interest in our cohort was a patient with EGFR-KDD who was histologically classified as cellular CMN. Although EGFR intragenic rearrangements are more commonly reported in classic and mixed subtypes, prior studies have demonstrated that EGFR-KDDs can also occur in a small subset of tumors with cellular morphology (5,9,15,17). In this case, the diagnosis of cellular CMN was supported by characteristic spindle-cell morphology with increased cellularity and mitotic activity, and was independently confirmed by experienced pediatric pathologists. This finding further illustrates the molecular and histologic overlap within CMN and underscores the importance of integrating morphologic and molecular features in diagnostic evaluation. Moreover, although EGFR-KDDs have been previously reported in CMN, including occasional cellular-type tumors, longitudinal data regarding treatment response remain scarce. Our case adds clinical detail regarding therapeutic resistance and subsequent disease stabilization with EGFR-directed therapy in a relapsed setting. The subsequent clinical response of this patient to EGFR-directed TKI therapy provides compelling evidence for the functional significance of this alteration (18,19). Our finding corroborates the emerging paradigm that CMN represents a molecular spectrum, and extends the work of Wegert et al. and van Spronsen et al. by demonstrating that EGFR-KDD can serve as the principal oncogenic driver even in histologically cellular tumors (5,20). This finding underscores the critical importance of comprehensive molecular profiling in relapsed or high-risk CMN, as it can unveil therapeutically actionable targets, such as EGFR-KDD, altering the clinical management and outcome for these patients.

In the absence of standardized postoperative management guidelines for relapsed or high-risk CMN, treatment decisions in our series were individualized and guided by molecular findings, prior therapies, and drug availability. The heterogeneous responses observed in these cases further underscore the clinical uncertainty in this setting and highlight the need for collaborative efforts to better define molecularly informed treatment strategies.

With respect to molecular testing, our findings do not support a uniform testing strategy for all CMN cases. Instead, they highlight the potential value of molecular analysis in selected clinical contexts, particularly in cellular or mixed subtypes, relapsed disease, or tumors with atypical presentation. Larger collaborative studies are needed to define the optimal scope and timing of molecular testing in CMN.

The limitations of this study include its retrospective, single-center design and the small patient cohort, which may underestimate the diversity of rare genetic fusions. Survival estimates should be cautiously interpreted, primarily serving to summarize follow-up outcomes rather than to substantiate prognostic inferences. Furthermore, heterogeneity in salvage treatments, influenced by patient condition and drug accessibility, complicates interpretation of therapeutic outcomes. Future multicenter collaborations with larger cohorts are needed to better define the prognostic impact of rare molecular subtypes and to evaluate emerging targeted and immunotherapeutic approaches.

Conclusions

This small single-center case series describes the clinical and molecular heterogeneity of CMN. While most patients experienced favorable outcomes following complete surgical resection, relapsed cases illustrated the challenges of managing molecularly atypical disease. These observations are descriptive in nature and underscore the need for larger collaborative studies to better define prognostic factors and therapeutic strategies in CMN.

Acknowledgments

We gratefully acknowledge the pathologists in our hospital for their expertise and generous provision of data.

Footnote

Reporting Checklist: The authors have completed the STROBE and AME Case Series reporting checklists. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-770/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-770/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-770/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-770/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Nanjing Medical University (No. 202509033-1) and informed consent was taken from all the patients’ legal guardians.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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