Mesoblastic Nephroma Research Articles

Imaging of Prenatal and Neonatal Intra-abdominal Genitourinary Tumors: a Review of the Literature.

Our goal was to summarize current literature related to imaging of intra-abdominal genitourinary tumors diagnosed in the prenatal or neonatal period. Our specific interests included modalities used, diagnoses made, changing incidence of tumor detection, and proposed future uses of these imaging modalities. Fetal and neonatal MRI have been used as an adjunct to ultrasound for better characterization and assessment of congenital mesoblastic nephroma, juvenile granulosa cell tumor, and other tumors. Despite recent literature describing fetal and neonatal MRI, it is not yet possible to determine whether its use is changing the incidence of tumor detection. Improvements in imaging technology, specifically the use of fetal MRI, have allowed for earlier identification of genitourinary masses with improved capability for diagnosis, surveillance, surgical planning, and sometimes prenatal treatment of the malignancy and related diagnoses, with a goal of preventing pregnancy and delivery complications.

Expanding the molecular spectrum of congenital mesoblastic nephroma: A rarely described KIAA1549::BRAF fusion in a classic variant

Congenital mesoblastic nephroma (CMN) are low grade spindle cell neoplasms with myofibroblastic differentiation and are classified morphologically as classic, cellular, or mixed. Recurrent genetic alterations have been identified – EGFR internal tandem duplication is associated with classic morphology, and ETV6::NTRK3 fusion is associated with the cellular subtype. We report a case of a classic variant of CMN with a rarely described KIAA1549::BRAF fusion.

Baby Girl with Mesoblastic Nephroma Kidney Tumor (NM)

AbstractBackground: Mesoblastic nephroma (NM) is the most common benign kidney tumor in infants, mostly occurring in the first six months of life; it is still very rare. These tumors are almost always diagnosed in children under two years of age. Radical nephrectomy as curative therapy.Case presentation: We report the case of a 22-day-old baby girl with complaints of enlarged abdomen which was known since the patient was born. The patient was born to G3P0A0 mother, 9 months of gestation, through normal delivery. Babies are born crying immediately. Birth weight 3100 grams. Abdominal examination, convex, normal bowel sounds, soft palpation, palpable solid mass on both flank, well defined, fixed, painless, size 15x15x10 cm. Renal ultrasound examination revealed bilateral renal masses ec DD/ Wilm's tumor, mesoblastic nephroma. Abdomen CT examination with contrast revealed a solid mass in the upper to lower abdomen bilaterally obliterating both kidneys, pressing the intestines to the middle abdomen, superiorly pressing the liver and spleen, anteriorly attached to the abdominal wall, posteriorly attached to the vertebral bodies ec DD/ mesoblastic nephroma, Wilm's tumor. Anatomical pathology examination revealed benign cystic lesions on both kidneys bilaterally.Conclusion: Radiological imaging has a major role in establishing the diagnosis of NM, so it will assist in the selection of fast and appropriate treatment.

Severe neonatal hypercalcemia revealing congenital mesoblastic nephroma: A case report and management of neonatal hypercalcemia: Severe neonatal hypercalcemia revealing congenital mesoblastic nephroma

Congenital mesoblastic nephroma is a rare pediatric renal tumor and has been reported in patients presenting with palpable abdominal mass, arterial hypertension, hematuria, polyuria, or hypercalcemia. Here we present the case of a 1-month-old neonate with suspected parathyroid hormone (PTH)-related peptide (PTH-rp)-mediated severe hypercalcemia revealing congenital mesoblastic nephroma. Preoperatively, hypercalcemia was corrected with hydration, furosemide, pamidronate, and low-calcium infant formula. Unilateral nephrectomy led to the resolution of hypercalcemia, transient hyperparathyroidism, and transient vitamin D and mineral supplementation. We conclude that congenital mesoblastic nephroma can secrete PTH-rp that can cause severe hypercalcemia.

Sructural rearrangements of NTRK genes: characteristics, methods of detection and targeted therapy for cancer

Background. The first-generation trk inhibitors, larotrectinib and entrectinib, were approved by the u.s. Food and drug administration (Fda) for the treatment of advanced solid tumors harboring NTRK gene fusions in November 2018 and in august 2019, respectively. The purpose of the study was to present upto-date data on the structure and functions of ntrk genes, the frequency of occurrence of rearrangements with their participation, the consequences of their occurrence at the cellular level, methods of detecting such rearrangements, as well as targeted drugs used in the presence of chimeric NTRK genes. Material and methods. A systemic literature search was conducted in pubmed ncbi, Web of science, scopus databases. Results. The products of NTRK genes are receptors for neurotrophins, and their high expression is normally observed only in a narrow range of tissue types. Intrachromosomal or interchromosomal rearrangements lead to a significant increase in the level of expression of the chimeric gene regulated by the strong promoter of the partner gene. The high transcriptional activity of such a gene, along with the constant activation of the kinase activity of the protein product, leads to the activation of metabolic pathways responsible for cell escape from apoptosis and disruption of the regulation of the cell cycle. The occurrence of chimeric NTRK genes varies between different types of tumors, with the highest (up to 90 %) in rare cancers (secretory carcinoma of the breast, secretory carcinoma of the salivary glands, congenital mesoblastic nephroma, children’s fibrosarcoma). Larotrectinib and entrectinib are highly effective targeted drugs in suppressing the growth of a tumor carrying NTRK rearrangements, regardless of the type of tumor. In this regard, the introduction of new high-precision methods for the detection of chimeric NTRK genes, as well as the study of the mechanisms of the development of resistance with the assumption of ways to overcome it, seems relevant. Conclusion. Rearrangements of NTRK genes are quite common in various types of oncology and are an effective target for modern targeted drugs.

Infantile fibrosarcoma with an EGFR kinase domain duplication: Underlining a close relationship with congenital mesoblastic nephroma and highlighting a similar morphological spectrum

Infantile fibrosarcoma (IFS) and congenital mesoblastic nephroma (CMN) are locally aggressive tumors primarily occurring in infants. Both IFS and the cellular subtype of CMN show overlapping morphological features and an ETV6-NTRK3 fusion, suggesting a close relationship. An activating alteration of EGFR, based on an EGFR kinase domain duplication (KDD), occurs in a subset of CMNs lacking an NTRK3 rearrangement, especially in the classic and mixed type. So far no EGFR-KDDs have been detected in IFS.We describe four pediatric tumors at the extremities (leg, n = 2; foot and arm n = 1) with histological features of IFS/CMN. Two cases showed classic IFS morphology while two were similar to classic/mixed type CMN. In all cases, an EGFR-KDD was identified without detection of a fusion gene. There were no abnormalities of the kidneys in any of the patients.This is the first description of IFS with an EGFR-KDD as driver mutation, supporting that IFS and CMN are similar lesions with the same morphological and genetic spectrum. Pathologists should be aware of the more fibrous variant of IFS, similar to classic/mixed type CMN. Molecular analyses are crucial to treat these lesions adequately, especially with regard to the administration of tyrosine kinase inhibitors.

ALK rearrangements in infantile fibrosarcoma-like spindle cell tumours of soft tissue and kidney.

Recurrent alterations in receptor tyrosine kinase (RTK) and downstream effectors are described in infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) and a subset of spindle cell sarcomas, provisionally designated 'NTRK-rearranged' spindle cell neoplasms. These two groups of tumours demonstrate overlapping morphologies and harbour alterations in NTRK1/2/3, RET, MET, ABL1, ROS1, RAF1 and BRAF, although their relationship is not fully elucidated. We describe herein a cohort of paediatric tumours with clinicopathological features not typical for inflammatory myofibroblastic tumour, but rather with similarities to cCMN/IFS harbouring ALK fusions. Clinicopathological features were assessed and partner agnostic targeted RNA sequencing on clinically validated platforms were performed. Tumours occurred in patients aged from 2 to 10 years (median age 2 years) with a 2:2 male to female ratio and an average size of 8.4 cm. Two tumours arose in soft tissues and two in the kidney. Morphological features included spindle to ovoid cells arranged in long fascicles or haphazardly within a myxoid to collagenised stroma; a subset of cases had either dilated, ectatic vessels or focal perivascular hyalinosis. By immunohistochemistry, all cases tested showed cytoplasmic expression of anaplastic lymphoma kinase (ALK) and one case demonstrated co-expression of CD34 and S100. This series of ALK-rearranged IFS-like tumours expands the spectrum of targetable kinases altered in these tumours and reinforces the potential overlap between IFS/cCMN-like tumours and the provisional entity of 'NTRK-rearranged' spindle cell neoplasms.

A Quaint Collation of Childhood Renal Neoplasms- Wilms and Beyond: Perspective of a Tertiary Care Hospital of Eastern India

Paediatric renal neoplasms are rarely encountered entities. Histopathology is essential in most of the cases, where there is significant degree of clinical and radiological overlap. Present series has 32 cases which aimed to evaluate clinical and pathologic spectrum of renal tumours in children. Nephrectomy specimens of renal neoplasms of children below 12 years of age were included. Haematoxylin and Eosin (H&E) staining and Immunohistochemistry (IHC) were done. Findings were tabulated in a master sheet along with other demographic variables, clinical histories and imaging findings. Abdominal lump was the commonest presentation. Wilms tumour was the major histologic variant (66%), followed by Congenital Mesoblastic Nephroma (13%). Anaplasia and advanced Children's Oncology Group (COG) staging were the adverse prognostic indicators. Clear Cell Sarcoma and Rhabdoid tumours were seen to have adverse outcomes, whereas Congenital Mesoblastic Nephroma, Multicystic Dysplastic Kidney and Paediatric Cystic Nephromas had overall favorable prognosis. Histopathology plays a key role for confirmatory opinion on nature of the neoplasm. Better understanding of these cases will increase the diagnostic accuracy with early implementation of definitive therapy.

Congenital mesoblastic nephroma beyond infancy

Congenital mesoblastic nephroma (CMN) is a peculiar renal tumor with a unique clinical, therapeutic, and prognostic pattern. CMN is a benign renal tumor of the neonatal period and early infancy. Although a rarity, presentations beyond infancy are also reported. Rarely, this tumor presents beyond infancy. The case report tries to highlight the fact that this tumor though rare beyond infancy should also be included in the list of differentials of childhood renal masses. It also underlines the utility of preoperative biopsy and the role of nephron-sparing surgery while dealing with such a benign etiology (considering the excellent prognosis associated with the condition).

Spectrum of pediatric kidney tumours with special references to WT1 immunostain at a tertiary care hospital.

Pediatric renal tumours are the second most common solid tumours in children. The most common in this group is Wilms tumour with mesoblastic nephroma being the 2nd most common tumour in children, younger than 3 months. The present study was conducted to study the epidemiological occurrence of pediatric renal tumours at a tertiary care hospital and to study the diagnostic efficacy of WT1 immunostaining in distinguishing Wilms tumour from other types of renal tumours. It was a single institution-based prospective and observational study conducted for 2 years (from October 2013 to September 2015) in the department of pathology in our hospital. A total of 50 cases were enrolled in this study all were below 15 years of age. Nephroblastoma or Wilms tumour was found to be the most common type, occurring in 66% cases. Fourteen out of 33 cases of Wilms tumour showed triphasic components (blastemal, epithelial, and stromal) with Blastemal type Wilms being the second most common (11 cases). WT1 immunostaining was positive in 93.9% cases of nephroblastoma. The highest amount of nuclear positivity noted in blastemal cells followed by epithelial cells. Rhabdomyoblastic differentiation and regressive variant showed nonspecific cytoplasmic staining. Cystic partially differentiated nephroblastoma and diffuse anaplasia type Wilms tumour showed nuclear staining in blastemal cells. The expression of WT1 immunostain was found to be diagnostically significant in differentiating Wilms tumour from other renal tumours.

In Vivo Imaging of Neo-angiogenesis of Transplanted Metastases in Subrenal Capsule Assay Induced Rat Model.

Changes in the expression of neo-angiogenic molecules in the primary tumor and its metastases may significantly affect the efficacy of therapies. The aim of this study was to evaluate the alterations in aminopeptidase N (APN/CD13) and αvβ3 integrin receptor expression in serially transplanted mesoblastic nephroma tumor (Ne/De) metastases using 68Gallium (68Ga)-labeled NOTA-cNGR and NODAGA-RGD radiotracers and preclinical positron emission tomography (PET) imaging. Primary and metastatic mesoblastic nephroma (Ne/De) tumors were induced by subrenal capsule assay (SRCA) in Fischer-344 rats. In vivo PET imaging experiments were performed 8±1 days after the SRCA surgery using intravenously injected 68Ga-NOTA-c(NGR), 68Ga-NODAGA-RGD, and [18F]FDG radiotracers. Among the examined neo-angiogenic molecules, the expression of αvß3 integrin in the tumors was significantly lower than that of APN/CD13. This observation was confirmed by the PET data analysis, where a 2-6-fold higher APN/CD13-specific 68Ga-NOTA-cNGR accumulation was observed in both primary malignancies and metastases. However, a steadily increased accumulation of [18F]FDG, 68Ga-NODAGA-RGD, and 68Ga-NOTA-cNGR was observed in the tumors growing under the renal capsule and in the metastatic parathymic lymph nodes during serial transplantations. The observed increase in 68Ga- NOTA-cNGR accumulation during serial transplantations correlated well with the western blot analysis, where APN/CD13 protein levels were also elevated in the metastatic parathymic lymph nodes. The observed increase in glucose metabolism and the up-regulated expression of αvß3 integrin and APN/CD13 during serial transplantations of metastases may indicate enhanced malignancy.

Renal tumours of childhood: A review

Renal tumours of childhood are rare, although they are one of the most common solid tumours in children. They include numerous entities, which have different clinical, histological, molecular biological and prognostic features, so their precise diagnosis and staging are critical for appropriate treatment. The most common is Wilms' tumour (WT) with ~80-85 % of all cases, whereas other entities including mesoblastic nephroma, clear cell sarcoma, rhabdoid tumour, renal cell carcinoma, metanephric tumours and others are very rare (2-4 % each) which explains why they represent a big diagnostic challenge for diagnostic pathologists. They are subclassified into three risk groups - low, intermediate and high - which have different treatments and prognosis. There are two big study groups which have different approaches but remarkable similar outcomes. The International Society of Paediatric Oncology approach (followed in most of the world) is based on preoperative chemotherapy, followed by surgery and further therapy, whereas the Children's Oncology Group approach (followed mainly in the United States and Canada) is based on primary surgery, followed by postoperative treatment.

Mesenchymal neoplasms with NTRK and other kinase gene alterations.

Kinase alterations are increasingly recognised as oncogenic drivers in mesenchymal tumours. Infantile fibrosarcoma and the related renal tumour, congenital mesoblastic nephroma, were among the first solid tumours shown to harbour recurrent tyrosine kinase fusions, with the canonical ETV6::NTRK3 fusion identified more than 20 years ago. Although targeted testing has long been used in diagnosis, the advent of more robust sequencing techniques has driven the discovery of kinase alterations in an array of mesenchymal tumours. As our ability to identify these genetic alterations has improved, as has our recognition and understanding of the tumours that harbour these alterations. Specifically, this study will focus upon mesenchymal tumours harbouring NTRK or other kinase alterations, including tumours with an infantile fibrosarcoma-like appearance, spindle cell tumours resembling lipofibromatosis or peripheral nerve sheath tumours and those occurring in adults with a fibrosarcoma-like appearance. As publications describing the histology of these tumours increase so, too, do the variety kinase alterations reported, now including NTRK1/2/3, RET, MET, RAF1, BRAF, ALK, EGFR and ABL1 fusions or alterations. To date, these tumours appear locally aggressive and rarely metastatic, without a clear link between traditional features used in histological grading (e.g. mitotic activity, necrosis) and outcome. However, most of these tumours are amenable to new targeted therapies, making their recognition of both diagnostic and therapeutic import. The goal of this study is to review the clinicopathological features of tumours with NTRK and other tyrosine kinase alterations, discuss the most common differential diagnoses and provide recommendations for molecular confirmation with associated treatment implications.

Neurotrophin Receptor Kinase: Updated Perspectives, Laboratory Considerations, and Clinical Implications

Neurotrophin Receptor Kinase: Updated Perspectives, Laboratory Considerations, and Clinical Implications

NTRK-Rearranged soft tissue neoplasms: A review of evolving diagnostic entities and algorithmic detection methods

The spectrum of tumors with NTRK1/2/3 rearrangements has expanded with widespread use of next generation sequencing (NGS) technology. For many years it was known that a majority of infantile fibrosarcomas (IFS), and their counterpart in the kidney, cellular congenital mesoblastic nephroma, contain the recurrent ETV6-NTRK3 fusion. Sequencing RNA transcripts from IFS and their morphologically similar counterparts in older children and adults has shown rearrangements with other 5′ partners combined with NTRK1, NTRK2, and NTRK3 can also occur. For those tumors occurring outside of the infant age group, this has resulted in a proposed new diagnostic entity of “NTRK-rearranged spindle cell neoplasm.” The clinical behavior of NTRK rearranged soft tissue tumors varies, though most show localized disease with rare metastases. The pathology of NTRK rearranged tumors exists on a spectrum, with overlapping features of classic infantile fibrosarcoma, lipofibromatosis, and malignant peripheral nerve sheath tumor. In this tumor spectrum, clinical and pathologic predictive factors are largely still to be determined, with no clear association between histologic grade and severity of disease. Of critical importance is detection of the NTRK rearrangement in order to guide treatment in patients with unresectable and metastatic disease. While resection is the definitive treatment, these tumors do show response to targeted TRK kinase inhibitors. Multiple detection methods are available, including immunohistochemistry, FISH, and next generation sequencing, which each have their merits and potential pitfalls. We aim to review the clinical characteristics and histomorphology of mesenchymal tumors with NTRK rearrangements as well as discuss molecular detection methods and diagnostic algorithms specific for soft tissue tumors.

VP12.09: Prenatal diagnosis of mesoblastic nephroma by sonography and magnetic resonance imaging

VP12.09: Prenatal diagnosis of mesoblastic nephroma by sonography and magnetic resonance imaging

Surgical management of cellular congenital mesoblastic nephroma in a neonate: a case report and review of literature

BackgroundCongenital mesoblastic nephroma (CMN) is the most common type of renal stromal tumor in neonates. It is classified into cellular, classical, and mixed types. The multidisciplinary management approach is the mainstay of management. We are reporting a case of neonatal congenital mesoblastic nephroma in a full-term boy with intrauterine growth restriction and hypertension managed effectively in our institution.Case presentationA full-term boy with intrauterine growth restriction (IUGR) with a birth weight of 2.3 kg, referred at birth with an abdominal mass. His antenatal scan at 35 weeks showed a cystic abdominal mass. On delivery, a huge visible abdominal mass of cystic consistency and smooth surface was noticed at the right side of the abdomen. blood pressure was 98/75 mmHg. It was responsive to hydralazine. Aldosterone and renin were significantly elevated at more than 100 and 500 ng/dl, respectively. Serum neurone-specific enolase (NSE) was 35 ng/ml while alfa feto protein was (AFP) 50,000 kIU/L. An abdominal ultrasound scan revealed an ill-defined large heterogeneous mass of 6.09 × 6.5 × 5.77 cm that arises from the right kidney. A computed tomography scan confirmed a right kidney mass with peripheral claw sign of the normal right renal tissue. It was crossing the midline and causing a mass effect on the adjacent structures. The right renal artery and vein were compressed and shifted posteriorly and inferomedially. Right radical nephrectomy was performed via a right lower transverse incision. The tumor was completely excised with a tumor weight of 270 g and a size of 10.5 × 8 × 5.5 cm. Histopathological diagnosis was mesoblastic nephroma of a cellular type which was confirmed by immunohistochemistry. Post-operatively, the blood pressure has significantly reduced and antihypertensive medications were eventually weaned off. The multidisciplinary team decided to preserve chemotherapy only in case of recurrence. At 3 months follow-up, no features of recurrence were noticed based on surveillance ultrasonography.ConclusionMesoblastic nephroma should be considered in any newborn with renal mass. The multidisciplinary team approach with aggressive management of hypertension, detailed radiological investigation, and complete tumor resection is fundamental for obtaining an excellent outcome for such entities.

A novel case of an infantile fibrosarcoma-like tumor with KIAA1549-BRAF translocation and an oncogenic NF2p.Q459* SNV with potential clinical significance

We report a case of a right gluteal mass from the sacroiliac joint to the knee of an infant girl. Biopsy showed histopathological features similar to infantile fibrosarcoma (IFS). However, unlike most IFS, no ETV6-NTRK3 fusion gene abnormality was detected. Molecular analysis with TruSight RNA Pan-Cancer Panel detected the presence of KIAA1549-BRAF translocation and an oncogenic NF2p.Q459* SNV with potential clinical significance. A review revealed that the combination of this patient’s tumor site with the presence of a KIAA1549-BRAF translocation abnormality and an accompanying single nucleotide variant has not been previously described. The detection of this translocation abnormality raises the possibility that the spindle cell tumors in infants with an absence of the ETV6-NTRK3 fusion gene abnormality might have a distinct pathogenetic mechanism different from the previously known IFS and congenital mesoblastic nephroma. Furthermore, the discovery of BRAF translocation and its aberrant signaling of the mitogen-activated protein kinase (MAPK) pathway in this tumor contributes to the promise of clinical benefit of using the MEKi trametinib for the treatment of progressive disease that is refractory to conventional chemotherapy.

Congenital Bilateral Wilms Tumor: A Case Report

Compare to congenital mesoblastic nephroma in fetus, congenital wilms tumor is extremely rare. Herein we report a case of congenital bilateral solid masses on antenatal ultrasound. The mass was evaluated by ultrasonography and contrast computed tomography scan in postnatal period, and the patient was undergoing tumor enucleation separately in short period after neoadjuvant chemotherapy. The diagnosis was confirmed by histology analysis for each side, and the treatment was taken according to the International Society of Pediatric Oncology.

An unusual fusion gene EML4-ALK in a patient with congenital mesoblastic nephroma.

Congenital mesoblastic nephroma (CMN), the most common renal tumor of infancy, is a mesenchymal neoplasm histologically classified into classic, cellular, or mixed types. Most cellular CMNs harbor a characteristic ETV6-NTRK3 fusion. Here, we report an unusual congenital mesoblastic nephroma presenting in a newborn boy with a novel EML4-ALK gene fusion revealed by Anchored Multiplex RNA Sequencing Assay. The EML4-ALK gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital mesoblastic nephroma, with yet another example of kinase oncogenic activation through chromosomal rearrangement. The methylation profile of the tumor corresponds with infantile fibrosarcoma showing the biological similarity of these two entities.