Poor outcome in congenital mesoblastic nephroma with TPM3::NTRK1 fusion: a case report from multi-disciplinary treatment to molecular tumor board

Introduction

Congenital mesoblastic nephroma (CMN) is a rare low-grade malignant kidney tumor in infants younger than 3 months, accounting for up to 87% of all renal tumors in the first 2 months of life (1-3). About 90% of children with CMN present with an abdominal mass and hematuria by their first birthday (4,5). The 5-year survival rate can reach over 90% for children with CMN who undergo complete surgical resection, making it the most ideal treatment for CMN (4-6).

However, there are still many factors affecting the prognosis of CMN, such as pathological type, fusion gene, and age (7). The pathological types of CMN can be divided into classic, cellular, and mixed types. Cellular CMN and infantile fibrosarcoma (IFS) share similar histopathological features and chromosomal aberration [t(12; 15) (p13; q25)] resulting in ETV6::NTRK3 fusion gene (8-12). Currently, ETV6::NTRK3 and trisomy 11 are the most common genetic abnormalities in CMN (4,10,13); other rare genetic abnormalities include EML4::NTRK3 (14), EML4::ALK (15), EGFR::KDD (16,17) and BRAF internal duplication (18).

The ETV6::NTRK3 translocation has been reported in extremity-based IFS (19,20), pediatric gastric mesenchymal sarcoma (21), papillary thyroid cancer (22), and pleomorphic xanthoastrocytoma (23), but it hasn’t been described in CMN. The CMN with TPM3::NTRK1 fusion gene reported in this study was initially observed, but it rapidly progressed following complete resection at 2+ years of age. A temporary response was achieved with treatment with the NTRK inhibitor, larotrectinib. This case is instructive that CMN should be treated promptly with surgery when feasible and target therapies may be helpful in the case of relapsed/refractory/progressive disease. We present this case in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-126/rc).

Case presentation

A boy with CMN was seen at Children’s Hospital of Nanjing Medical University. Prenatal ultrasonography at 37 weeks of gestation revealed that the child had a right renal mass. Ultrasonography revealed a mass measuring approximately 2.6 cm × 1.8 cm after birth. At that time, we communicated with the parents and informed them that there were two treatment options: surgical resection or close follow-up. We explained in detail the pros and cons of both options to the parents, who preferred close follow-up, with an ultrasonography reexamination scheduled every 3–6 months until the child reaches 22 months of age, and the size of tumor was stable for several months prior to that based on regular ultrasonography. When the child was 28 months old, he was admitted to the hospital due to recurrent fevers and rapid enlargement of the renal mass. Abdominal computed tomography (CT) suggested that the volume of the right kidney had increased, and a low-density shadow could be seen in the superior portion of the right kidney, with a size of approximately 5.3 cm × 6.4 cm × 5.5 cm. Mild enhancement and multiple vascular shadows inside the tumor could be seen in the arterial phase (Figure 1). No enlarged lymph nodes were detected in the retroperitoneal space. No metastatic lesions were found in the cerebrum, lungs, spine, liver, gallbladder, pancreas, spleen, kidney, or bone marrow according to CT, magnetic resonance imaging (MRI), B-ultrasound, and bone marrow examination. There were no significant abnormalities in the serum levels of carbohydrate antigen 19-9 (CA19-9), neuron-specific enolase (NSE), alpha fetoprotein (AFP), and carcinoembryonic antigen (CEA). We organized multi-disciplinary treatment (MDT) after a thorough examination and ultimately concluded that the tumor could be completely removed after the evaluation by the Department of Urology, Hematology, and Radiology. We believe that based on the rate of tumor’s progression, there is a higher likelihood of malignancy. Therefore, the tumor could be a Wilms’ tumor, neuroblastoma, or renal sarcoma. Given the age of onset, any of these three types of tumors could occur. Based on the CT results, the tumor is most likely originating from the kidney, thus indicating a higher likelihood of Wilms’ tumor or renal sarcoma. However, the possibility of neuroblastoma originating from the adrenal gland on one side invading the kidney cannot be ruled out. The phenomenon of neuroblastoma compressing one kidney is more common, while the rapid and extensive invasion of renal tissue in a short time is uncommon. The right kidney was subsequently resected and a retroperitoneal lymph node dissection was performed. The pathological results indicated that the tumor capsule was intact and the tumor had invaded the renal pelvis (Figure 2A). No tumor cells were detected in the cutting edge and lymph nodes that were adjacent to the right renal hilum, inferior vena cava, and abdominal aorta. Hematoxylin-eosin staining showed diffused proliferative round tumor cells and bundled spindle tumor cells in the field of view (Figure 2B). Immunohistochemistry showed pan-NTRK (+++) (Figure 2C), pan-cytokeratin (pan-CK) (−), TLE1 (−), SATB2 (−), BCOR (−), WT-1 (−), CK (−), epithelial membrane antigen (EMA) (−), vimentin (partial+), desmin (−), CD99 (+), SMARCB1 (+), CyclinD1 (−), NSE (−), leukocyte common antigen (LCA) (scattered+), and Ki67 (30%+). These morphological features were consistent with the diagnosis of cellular CMN. Molecular analysis was performed and was negative for rearrangements of ETV6, NTRK2, and NTRK3, but positive for rearrangement of NTRK1 (Figure 2D-2F). To identify the fusion partners of NTRK1 and other potential abnormal genes, a screen was performed evaluating 231 genes, 120 fusion products, 17 amplifications, and 24 variant genes on Illumina HiSeqX PE 150 bp platform (Illumina, San Diego, CA, USA). The results revealed a TPM3::NTRK1 fusion gene (Figure 3). According to the pathological and molecular characteristics, an MDT including the Departments of Hematology, Oncology, Pathology, Urology and Radiology was organized, and a watchful waiting surveillance plan was adopted based on the good prognosis and complete resection of the tumor.

Figure 1 CT scan of the child confirmed a tumor of the left kidney. (A) Axial arterial phase contrast-enhanced CT image of the abdomen showed a large mass in the right kidney (down arrow). (B) Coronal reconstructed image showed a mildly enhanced mass in the superior of the right kidney (down arrow). CT, computed tomography.

Figure 2 Pathological and molecular characteristics of this tumor. (A) The vertical section of this tumor showed an invasion of the right renal pelvis. (B) Hematoxylin-eosin staining (×200) showed diffused proliferative round tumor cells and bundled spindle tumor cells in the field of vision. (C) Pan-TRK staining (×200) showed a strong cytoplasmatic positivity of immunohistochemical marker pan-TRK among tumor cells. (D-F) Break-apart FISH analysis (×1,000) for NTRK1 (D), NTRK2 (E), and NTRK3 (F) rearrangements confirmed NTRK1 rearrangement (red probe for 3' and green probe 5'): The proportion of cell with the abnormal signal of 2F1R (2 fusion 1 red) reached to 47% for NTRK1 and the proportion of cell with 2F (2 fusion) signal reached to 99% for NTRK2 and for NTRK3. TRK, tropomyosin receptor kinase; FISH, fluorescence in-situ hybridization.

Figure 3 Sequencing results of TPM3-NTRK1 fusion gene. Sequencing analysis of TPM3-NTRK1 fusion gene illustrated that the fusion occurred between exon 1–8 of TPM3 (chromosome 1) and exon 10–17 of NTRK1 (chromosome 1).

No metastases were found 2 months after surgery, but a right retroperitoneal mass and liver (Figure 4A,4B) and lung metastases were detected 3 months after surgery. Considering that there was no uniform chemotherapy protocol for CMN, the patient was treated with vincristine, epirubicin, cyclophosphamide, and dactinomycin after discussion. The metastases in the retroperitoneum, liver, and lungs continued to grow despite treatment, and there was a decrease in muscle strength in both lower limbs due to the thoracic vertebral metastasis after two courses of chemotherapy (Figure 4C). We organized a molecular tumor board (MTB) including the Departments of Pathology, Hemato-oncology, Urology, and Radiology, and selected the drug larotrectinib targeting tropomyosin receptor kinase (TRK) because of the rapid progression. Following initiation of treatment with larotrectinib, it was found that the lesions in the right retroperitoneum, liver (Figure 4D), and lungs (Figure 5A-5D) were significantly reduced, and the intraspinal mass in T5–T7 did not further enlarge during 4 months of larotrectinib administration. The child eventually developed fever, diarrhea, skin ulcers, and oxygen hyposaturation rapidly, and CT chest showed significant progression of pulmonary metastases 5 months after larotrectinib administration (Figure 5E). The patient was transitioned to received palliative treatment and died 2 months later.

Figure 4 Tumor recurrence and efficacy of larotrectinib. (A) CT scan showed CMN recurrence in the right retroperitoneum 3 months after surgery (down arrow). (B) CT scan showed liver metastasis 3 months after surgery (right arrow). (C) MRI indicated epidural lesion of T5–T7 after two courses of chemotherapy (left arrow), and CMN metastasis was considered. (D) Changes in the size of right retroperitoneal and liver lesions from the time of recurrence to 4 months after larotrectinib administration. CT, computed tomography; CMN, congenital mesoblastic nephroma; MRI, magnetic resonance imaging.

Figure 5 Changes in pulmonary metastatic lesions during the course of the disease. (A) We did not detect any lung metastasis before surgery. (B) Multiple lung metastases were observed 3 months after surgery. (C) The pulmonary metastatic lesions were still progressing after two courses of chemotherapy. (D) We found a significant reduction in the number and size of lung metastases after 3 months of using larotrectinib alone. (E) The pulmonary metastases progressed again rapidly after 5 months of larotrectinib administration.

All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of Children’s Hospital of Nanjing Medical University (ethical approval No. 202306001-1) and with the Helsinki Declaration (as revised in 2013). Written informed consent was provided by the patient’s legal guardian for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

International multidisciplinary team (iMDT) discussion

Currently, for patients with a confirmed diagnosis of CMN, early surgery can achieve desirable treatment outcomes. Numerous clinical studies have proven this conclusion (1-6), which is also the advantage of early surgery. However, for patients with an unclear diagnosis, the decision to proceed with surgical treatment still needs to be approached cautiously. Some benign tumors can stabilize long-term, and there is even a possibility of spontaneous regression in some cases of neuroblastoma. For these newborns, aggressive surgical treatment could lead to significant trauma. The strong willingness of the parents to follow-up observation, and the results of 1–2 rechecks of ultrasounds showing no significant increase in the tumor, have increased the parents’ confidence in conservative treatment for the child. These are the main reasons why we did not perform early surgery. An initial watchful waiting approach was adopted in this case, and the patient rapidly progressed after 2+ years of observation. This experience suggests that even if a tumor behaves in an indolent manner initially, it is prudent to proactively perform surgery on any patient with a high suspicion of CMN. Previous literature has shown that cellular CMNs are more malignant and more likely to achieve distant metastasis than classical and mixed CMNs (8). While CMN is typically considered a low-grade malignant tumor (24), its properties may change over time and prompt surgical management is indicated.

We report a rare cellular CMN with TPM3::NTRK1 fusion gene for the first time through this study. The immunohistochemical results of pan-TRK (+++) indicated that there might be rearrangement of NTRK, which has been shown to be the most common fusion gene in cellular CMN (3,4,8-10,13,16). The fluorescence in-situ hybridization (FISH) results showed that there was no rearrangement of NTRK3 and ETV6, but sequencing revealed a rearrangement of NTRK1 in this case. NTRK1 rearrangement has not been reported in cellular CMN in the literature, indicating that this might be a newly discovered molecular subtype of CMN with NTRK1 rearrangement. The TPM3::NTRK1 fusion gene has been frequently reported in adult cancers (25-30), where it is associated with a poor prognosis (30). Our literature review located few reports of pediatric tumors with TPM3::NTRK1 fusion gene and no reports on CMNs with TPM3::NTRK1 fusion gene (21-23). Previous studies have found that cellular CMN and IFS are similar histologically, and they are both commonly associated with the ETV6::NTRK3 translocation (8,17). Some scholars even believe that cellular CMN is a special type of IFS developing in the kidneys (8). Interestingly, there have been reports of IFS with the TPM3::NTRK1 fusion gene (19,20) identified in our patient.

The lesions in the lungs, liver, and posterior peritoneum were significantly reduced through the treatment of larotrectinib. The tumor progressed again 5 months later and the child was admitted to the palliative care unit with parental consent. Previous studies have shown that the rapid progression of solid tumors with NTRK fusion gene after treatment with type I TRK inhibitors is due to the mutant sites in F589L, G595R, G667C, G667S, and A608D of TRKA kinase (31-33), and we consider that the progression of this CMN 5 months after treatment with larotrectinib may be related to this mechanism. However, we were unable to verify this hypothesis through genetic testing due to the lack of consent from the child’s guardian. With the development of the second-generation type I TRK inhibitor, especially the application of LOXO-195 and TPX-0005 in clinical trials (34-37), we hope to greatly reduce the drug resistance caused by site mutations of TRKA kinase.

Discussion among physicians from Children’s Hospital of Nanjing Medical University

Department of Urology

Malignant tumors originating from the kidneys in children include Wilms’ tumor, CMN, cystic nephroma, and renal rhabdomyosarcoma. Based on the patient’s clinical presentation, we first considered the possibility of CMN. Following the patient’s admission, further examinations revealed that the tumor was localized to one side of the kidney, with extensive infiltration into the renal parenchyma, but no distant metastasis. Therefore, the chosen surgical approach was nephrectomy of the affected kidney along with lymph node biopsy. The tumor was completely resected during surgery, and postoperative pathology indicated that the tumor had not breached the capsule and there was no tumor cell infiltration in the lymph nodes, demonstrating the successful achievement of complete tumor resection. However, the child experienced a local recurrence at the primary site after 3 months postoperatively, with multiple liver and lung metastases. Despite chemotherapy, rapid disease progression occurred. This outcome suggests a high degree of malignancy and rapid progression of the tumor, as well as insensitivity to chemotherapy agents, which contradicts our traditional understanding of CMN.

Department of Radiology

After the child was admitted to the hospital, a contrast-enhanced CT scan revealed a relatively large solid mass in the upper pole of the right kidney, measuring approximately 77 mm × 62 mm × 75 mm, which had increased in size compared to previous examinations. The CT value of the mass was approximately 20–40 Hounsfield unit (HU), and it contained multiple small linear low-density shadows with clear borders. The enhancement of the mass was uneven, and there were multiple tortuous small vascular shadows inside, with the solid portion of the mass having a CT value of approximately 40–100 HU. No obvious enlarged lymph nodes were observed, but there was slight displacement of the inferior vena cava due to compression. The preliminary diagnosis is a possible Wilms’ tumor or a CMN. A subsequent CT scan, when the child had a recurrence, showed a soft tissue density mass in the right retroperitoneum, measuring approximately 6.9 cm × 7.7 cm, with uneven enhancement after contrast. There was also a round mixed low-density shadow of unclear border in the left lobe of the liver, measuring approximately 7.3 mm × 5.8 mm, with uneven enhancement at the edge after contrast, as well as multiple nodules in both lungs. The MRI results showed an extradural mass at the T5–T7 thoracic vertebrae, indicating possible tumor metastasis.

Department of Pathology

The pathology results of the patient show that the tumor invaded the renal pelvis, but did not penetrate the renal capsule, and no metastasis was found in the ureter or surrounding tissues. HE staining showed diffuse proliferation of round tumor cells and spindle-shaped tumor cells arranged in bundles in the tumor. The diagnosis is considered to be CMN. The tumor is positive for TPM3::NTRK1 fusion gene, with strong positive NTRK immunostaining and negative CyclinD1, further supporting the diagnosis of CMN. This tumor is rare, with an extremely low incidence, and it has been reported that most cases are low-grade malignant, but there are also a few malignant cases. After undergoing chemotherapy, the tumor rapidly progressed. Considering the fusion gene status, targeted TRK therapy may be considered for treatment.

Department of Hematology and Oncology

The child has a long medical history, with a renal mass detected at 37 weeks of gestation. After birth, regular follow-ups showed no change in the size of the tumor. In October 2019, there was a rapid increase in the size of the mass. Following a multidisciplinary assessment, the child underwent a right nephrectomy and lymph node biopsy. Post-surgery pathology indicated no tumor metastasis and suggested a diagnosis of CMN with a positive TPM3::NTRK1 fusion gene. Three months after surgery, there was a recurrence of the tumor. CMN is a rare, mostly low-grade malignant tumor with no established chemotherapy regimens. In most cases, treatment recommendations rely on the experience of other research centers. After internal discussions, the child received vincristine, epirubicin, cyclophosphamide, and dactinomycin chemotherapy, which showed limited effectiveness. Considering the rapid progression of the tumor and the positive TPM3::NTRK1 fusion gene, it was decided to initiate treatment with TRK targeted therapy based on the advice of the pathology department.

Several questions arise concerning the diagnosis and treatment of this patient

Question 1. Some scholars have proposed that cellular CMN is a special type of IFS. The current evidence supporting this viewpoint is that both types of tumors show an abundance of spindle-shaped cells in their pathological results, and they have similar fusion gene types. Personally, I believe that these pieces of evidence are not sufficient. Therefore, I am curious to know if there is any other evidence currently available to support this viewpoint

Expert opinion 1: Dr. David Van Mater

IFS and cellular CMN both have a “sarcoma-like” histology. Both lesions are generally curable with complete resection and commonly share NTRK translocations. However, it remains unknown if IFS and cellular CMN represent the same neoplasm arising in a different site or if they simply share some features but remain biologically distinct.

Expert opinion 2: Dr. Laura S. Hiemcke-Jiwa

The arguments that support a close relationship between IFS and CMN are: (I) similar clinical characteristics (both infants); (II) similar morphology, including composite IFS cases mimicking classic/mixed CMN; (III) similar molecular alterations including ETV6::NTRK3 and EGFR kinase domain duplications (KDDs); (IV) similar RNA expression profile (see https://doi.org/10.1016/j.anndiagpath.2021.151885).

Question 2. CMN has long been considered a tumor with a good prognosis, but in this study, this particular case had a poor prognosis. Currently, there is no consensus on the treatment approach for CMN with a poor prognosis among different medical institutions. The chemotherapy regimen we adopted in this study was also based on previous literature reports. Therefore, the question arises as to whether there is a standardized and effective treatment approach for CMN

Expert opinion 1: Dr. David Van Mater

While there is no standard chemotherapy regimen, I think there is consensus that surgery should be utilized upfront. Larotrectinib is Food and Drug Administration-approved for the treatment of any tumor with a NTRK fusion. It is a very rational approach (especially in light of the similarities to IFS).

Question 3. Larotrectinib is an effective targeted drug for tumors with NTRK fusion genes. However, resistance to larotrectinib is also a challenge faced by clinicians. With the use of second-generation TRK inhibitors such as LOXO-195, this problem can be resolved. Therefore, in order to prevent pediatric patients with tumors from facing a situation where they have no effective treatment options due to resistance to second-generation TRK inhibitors, it is worth exploring whether a treatment regimen combining larotrectinib with other targeted drugs is feasible in preclinical research on CMN

Expert opinion 1: Dr. David Van Mater

There may be some merit to this idea of combining larotrectinib with other agents, but I think it is beyond the scope of this paper. I think it would be more interesting to prove that this patient developed a mutation in NTRK1 rendering it resistant to larotrectinib, but that was not feasible as you noted.

Conclusions

With the development of second-generation sequencing and microarray technique, increasing attention has been paid to the personalized treatment of tumor based on molecular typing. As a special type of MDT, MTB addresses the problems of tumor diagnosis and treatment at the molecular level, and it has played an important role in the precision diagnosis and treatment of various tumors in recent years (38,39). Gooskens et al. found that the histological subtype was the most important factor affecting the prognosis of CMN, and cellular CMN had the worst prognosis among all CMN subtypes (40). CMN has multiple types of genetic abnormalities, with NTRK rearrangement being the most common type of genetic abnormality. Therefore, personalized treatment based on these abnormal molecular phenotypes will bring new treatments to recurrent and refractory CMN. Our literature review revealed one case of larotrectinib being used in the treatment of CMN with ETV6::NTRK3 fusion gene, and the patient had a good response (41). Albert et al. also asserted that CMN with NTRK rearrangement is a suitable target for TRK inhibitors (42). The case in this study was a rare cellular CMN with TPM3::NTRK1 fusion gene, metastatic spread, and poor response to traditional chemotherapy. Molecular-targeted therapy based on MTB induced a partial response and delayed progression, though it ultimately did not impact survival. This result demonstrates that personalized therapy based on MTB is feasible and effective in the diagnosis and treatment of CMN.

Acknowledgments

Funding: This study was supported by the General Project of Nanjing Medical University (grant No. NMUB20210060), National Natural Science Foundation of China (grant No. 81903383), Natural Science Foundation of Jiangsu Province (grant No. BK20211009), Scientific Research Projects of Jiangsu Health Commission (grant No. ZDB2020018), China Postdoctoral Science Foundation Funded Project (grant No. 2021M701764), Special Fund for Health Science and Technology Development in Nanjing (grant No. JQX19008), and Nanjing Medical Science and Technology Development Project (grant No. YKK21149).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-126/rc

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-126/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. All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of Children’s Hospital of Nanjing Medical University (ethical approval No. 202306001-1) and with the Helsinki Declaration (as revised in 2013). Written informed consent was provided by the patient’s legal guardian for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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/.

References

1. Serra G, Cimador M, Giuffrè M, et al. Report and follow-up on two new patients with congenital mesoblastic nephroma. Ital J Pediatr 2023;49:124. [Crossref] [PubMed]
2. Bolande RP, Brough AJ, Izant RJ Jr. Congenital mesoblastic nephroma of infancy. A report of eight cases and the relationship to Wilms' tumor. Pediatrics 1967;40:272-8.
3. Tongsong T, Palangmonthip W, Chankhunaphas W, et al. Prenatal Course and Sonographic Features of Congenital Mesoblastic Nephroma. Diagnostics (Basel) 2022;12:1951. [Crossref] [PubMed]
4. Jiang H, Zhao X, Liao W, et al. Hematuria due to the congenital mesoblastic nephroma: A rare case report. Asian J Surg 2022;45:2302-3. [Crossref] [PubMed]
5. Rayner J, Vinycomb T, Wanaguru D, et al. Congenital mesoblastic nephroma: review of current management and outcomes in a single centre. ANZ J Surg 2023;93:1008-11. [Crossref] [PubMed]
6. Vokuhl C, Nourkami-Tutdibi N, Furtwängler R, et al. ETV6-NTRK3 in congenital mesoblastic nephroma: A report of the SIOP/GPOH nephroblastoma study. Pediatr Blood Cancer 2018;
7. Furtwaengler R, Reinhard H, Leuschner I, et al. Mesoblastic nephroma--a report from the Gesellschaft fur Pädiatrische Onkologie und Hämatologie (GPOH). Cancer 2006;106:2275-83. [Crossref] [PubMed]
8. Bayindir P, Guillerman RP, Hicks MJ, et al. Cellular mesoblastic nephroma (infantile renal fibrosarcoma): institutional review of the clinical, diagnostic imaging, and pathologic features of a distinctive neoplasm of infancy. Pediatr Radiol 2009;39:1066-74. [Crossref] [PubMed]
9. Rubin BP, Chen CJ, Morgan TW, et al. Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. Am J Pathol 1998;153:1451-8. [Crossref] [PubMed]
10. Liu T, Al-Kzayer LFY, Sarsam SN, et al. Cellular congenital mesoblastic nephroma detected by prenatal MRI: a case report and literature review. Transl Pediatr 2022;11:163-73. [Crossref] [PubMed]
11. Knezevich SR, Garnett MJ, Pysher TJ, et al. ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res 1998;58:5046-8.
12. Tan SY, Al-Ibraheemi A, Ahrens WA, et al. ALK rearrangements in infantile fibrosarcoma-like spindle cell tumours of soft tissue and kidney. Histopathology 2022;80:698-707. [Crossref] [PubMed]
13. Anderson J, Gibson S, Sebire NJ. Expression of ETV6-NTRK in classical, cellular and mixed subtypes of congenital mesoblastic nephroma. Histopathology 2006;48:748-53. [Crossref] [PubMed]
14. Church AJ, Calicchio ML, Nardi V, et al. Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy. Mod Pathol 2018;31:463-73. [Crossref] [PubMed]
15. Misove A, Vicha A, Zapotocky M, et al. An unusual fusion gene EML4-ALK in a patient with congenital mesoblastic nephroma. Genes Chromosomes Cancer 2021;60:837-40. [Crossref] [PubMed]
16. Lei L, Stohr BA, Berry S, et al. Recurrent EGFR alterations in NTRK3 fusion negative congenital mesoblastic nephroma. Pract Lab Med 2020;21:e00164. [Crossref] [PubMed]
17. van Spronsen R, Kester LA, Knops RRG, et al. Infantile fibrosarcoma with an EGFR kinase domain duplication: Underlining a close relationship with congenital mesoblastic nephroma and highlighting a similar morphological spectrum. Ann Diagn Pathol 2022;57:151885. [Crossref] [PubMed]
18. Zhao M, Yin M, Kuick CH, et al. Congenital mesoblastic nephroma is characterised by kinase mutations including EGFR internal tandem duplications, the ETV6-NTRK3 fusion, and the rare KLHL7-BRAF fusion. Histopathology 2020;77:611-21. [Crossref] [PubMed]
19. Davis JL, Lockwood CM, Stohr B, et al. Expanding the Spectrum of Pediatric NTRK-rearranged Mesenchymal Tumors. Am J Surg Pathol 2019;43:435-45. [Crossref] [PubMed]
20. Davis JL, Lockwood CM, Albert CM, et al. Infantile NTRK-associated Mesenchymal Tumors. Pediatr Dev Pathol 2018;21:68-78. [Crossref] [PubMed]
21. Atiq MA, Davis JL, Hornick JL, et al. Mesenchymal tumors of the gastrointestinal tract with NTRK rearrangements: a clinicopathological, immunophenotypic, and molecular study of eight cases, emphasizing their distinction from gastrointestinal stromal tumor (GIST). Mod Pathol 2021;34:95-103. [Crossref] [PubMed]
22. Beimfohr C, Klugbauer S, Demidchik EP, et al. NTRK1 re-arrangement in papillary thyroid carcinomas of children after the Chernobyl reactor accident. Int J Cancer 1999;80:842-7. [Crossref] [PubMed]
23. Pehlivan KC, Malicki DM, Levy ML, et al. TPM3-NTRK1 fusion in a pleomorphic xanthoastrocytoma presenting with haemorrhage in a child. BMJ Case Rep 2020;13:e234347. [Crossref] [PubMed]
24. Isaacs H Jr. Fetal and neonatal renal tumors. J Pediatr Surg 2008;43:1587-95. [Crossref] [PubMed]
25. Wu S, Liu Y, Shi X, et al. Elaboration of NTRK-rearranged colorectal cancer: Integration of immunoreactivity pattern, cytogenetic identity, and rearrangement variant. Dig Liver Dis 2023;55:1757-64. [Crossref] [PubMed]
26. Zhao R, Yao F, Xiang C, et al. Identification of NTRK gene fusions in lung adenocarcinomas in the Chinese population. J Pathol Clin Res 2021;7:375-84. [Crossref] [PubMed]
27. Vargas AC, Ardakani NM, Wong DD, et al. Chromosomal imbalances detected in NTRK-rearranged sarcomas by the use of comparative genomic hybridisation. Histopathology 2021;78:932-42. [Crossref] [PubMed]
28. Rabban JT, Devine WP, Sangoi AR, et al. NTRK fusion cervical sarcoma: a report of three cases, emphasising morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma. Histopathology 2020;77:100-11. [Crossref] [PubMed]
29. Gatalica Z, Xiu J, Swensen J, et al. Molecular characterization of cancers with NTRK gene fusions. Mod Pathol 2019;32:147-53. [Crossref] [PubMed]
30. Lasota J, Chłopek M, Lamoureux J, et al. Colonic Adenocarcinomas Harboring NTRK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 16 Cases and Review of the Literature. Am J Surg Pathol 2020;44:162-73. [Crossref] [PubMed]
31. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018;15:731-47. [Crossref] [PubMed]
32. Wang ZZ, Wang MS, Wang F, et al. Exploring the kinase-inhibitor fragment interaction space facilitates the discovery of kinase inhibitor overcoming resistance by mutations. Brief Bioinform 2022;23:bbac203. [Crossref] [PubMed]
33. Somwar R, Hofmann NE, Smith B, et al. NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors. Commun Biol 2020;3:776. [Crossref] [PubMed]
34. Drilon A, Nagasubramanian R, Blake JF, et al. A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov 2017;7:963-72. [Crossref] [PubMed]
35. O'Donohue TJ, Ibáñez G, Coutinho DF, et al. Translational Strategies for Repotrectinib in Neuroblastoma. Mol Cancer Ther 2021;20:2189-97. [Crossref] [PubMed]
36. Liu Z, Yu P, Dong L, et al. Discovery of the Next-Generation Pan-TRK Kinase Inhibitors for the Treatment of Cancer. J Med Chem 2021;64:10286-96. [Crossref] [PubMed]
37. Drilon A, Ou SI, Cho BC, et al. Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. Cancer Discov 2018;8:1227-36. [Crossref] [PubMed]
38. Tamborero D, Dienstmann R, Rachid MH, et al. The Molecular Tumor Board Portal supports clinical decisions and automated reporting for precision oncology. Nat Cancer 2022;3:251-61. [Crossref] [PubMed]
39. Luchini C, Lawlor RT, Milella M, et al. Molecular Tumor Boards in Clinical Practice. Trends Cancer 2020;6:738-44. [Crossref] [PubMed]
40. Gooskens SL, Houwing ME, Vujanic GM, et al. Congenital mesoblastic nephroma 50 years after its recognition: A narrative review. Pediatr Blood Cancer 2017; [Crossref]
41. Halalsheh H, McCarville MB, Neel M, et al. Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma. Pediatr Blood Cancer 2018;65:e27271. [Crossref] [PubMed]
42. Albert CM, Davis JL, Federman N, et al. TRK Fusion Cancers in Children: A Clinical Review and Recommendations for Screening. J Clin Oncol 2019;37:513-24. [Crossref] [PubMed]