Congenital mesoblastic nephroma (CMN) is the most common mesenchymal pediatric renal neoplasm with low malignant potential, in the first month of life. ^1,2

Less than 5% of all pediatric renal tumors. Median age of diagnosis is earlier in classic CMN (6-17 days), compared to mixed (1.9 m) and cellular (3.7-5m) variants; 15% of the cases are detected prenatally. Male to female ratio is 1.5:1.¹ Associated congenital anomalies have been reported in a minority of cases (mostly genitourinary or gastrointestinal anomalies, Beckwith–Wiedemann syndrome OMIM:130650

CMN typically presents a unilateral, solitary, palpable abdominal mass, arising in the region of renal sinus. Less frequent symptoms are hypertension (19%) and hematuria (11%), rarely hypercalcemia (4%) and hyperreninemia (1%). Congenital forms can be identified in utero by ultrasound and may present with fetal hydrops and polyhydramnios. ¹

CMNs are composed of uniform, elongated spindle cells in bundles, with entrapped glomeruli and tubules. There are three morphological variants: a) classic (24%) (benign, with low cellularity), b) cellular (64%) (with low malignant potential) and c) mixed (10%). Classical and cellular variants are morphologically identical to infantile fibrosarcoma. ³ ‘Herring bone’ pattern is often observed, particularly in cellular variant.

CMN variably express vimentin, smooth muscle actin, and muscle specific actin.  Cyclin D1 and beta-catenin may be useful markers for differentiating between cellular CMN and classic CMN when the histology is not conclusive. ⁴ pan-Trk antibody expression to TRK fusion detection is reliably as RT-PCR and FISH. ⁵

Most cellular or classic CMN are localized at diagnosis and are treated by surgery only. Preoperative chemotherapy may be an option in small patients at high risk for surgery. 5 year overall survival is 95%, with recurrences or metastases occurring in 4% generally within the first year. Death is related to treatment toxicity in younger patients. Advanced stage (Stage III), cellular subtype, age >3 months have a potential negative influence on outcome

Recent development of selective TRK inhibitors, such as Larotrectinib (LOXO-101), which demonstrated a 75% response rate across children and adults with TRK fusion cancers. ⁶ The recent findings of EGFR alterations in NTRK negative CMN ⁷ suggest that targeted therapy with EGFR inhibitor, as Afatinib, is an option.

A cryptic t(12;15)(p13;q25) (Fig.1) associated with ETV6::NTRK3 gene fusion  occurs almost exclusively in cellular CMN, ⁸ but  gene fusion rearrangement has not been consistently demonstrated. ²
Trisomy 11 has been identified, as additional aberration, mainly in 29% of cellular/mixed morphological variants . Other recurrent reported aberrations were all trisomies (e.g. 8, 17, 20, 7, 18, 2 and 9) only in the mixed/cellular type CMN.³

Fig.1: This t(12;15)(p13;q26) is a characteristic translocation in congenital mesoblastic nephroma. (A) This is a cryptic translocations; therefore, FISH analysis using the ETV6 probe at 12p13 is necessary to confirm the translocations either in (B) metaphase chromosomes or in (C) intherphase nuclei (Courtesy of Dr.Jonathan Fletcher). 

Single cases have been also reported with NTRK1-3 ⁹ and BRAF rearrangements. ¹⁰
Recurrent EGFR alteration and BRAF-IDT, in CMN negative by canonical ETV6::NTRK3 rearrangement. ^7,10,11

So far, the same t(12;15)(p13;q25) /ETV6::NTRK3 fusion have been  reported also  in infantile fibrosarcoma, secretory breast cancer, mammary analogue secretory carcinoma of the salivary gland, papillary thyroid carcinoma, inflammatory myofibroblastic tumors, skin melanocytic tumor, brain tumors, colon carcinoma, as well as in hematologic malignancies.
Mesenchymal tumors with NTRK -rearrangement has been recognized in a variety of mesenchymal tumors.¹²