CMN is the most frequently diagnosed renal tumor in the first 5 months of life, and it may also be evidenced prenatally [1]. However, it is rarely detected by mid-pregnancy US (20 WG) [7, 18], while more commonly it may be indirectly revealed through the co-occurrence of polyhydramnios, commonly observed during the third trimester [4]. In the present patients, polyhydramnios was found only in the first case, referring to the fetal left renal mass. In the second case no antenatal diagnosis was made, and the first signs of disease were an asymptomatic palpable abdominal mass, along with poor feeding and growth. Polyhydramnios can result in preterm labor and delivery, as occurred in our first case, contributing to a more complex management of patients due to the neonatological issues associated with prematurity.
Urinary catecholamine assay and serum NSE, resulted normal in both our patients, are essential since neuroblastoma represents the most frequent extracerebral solid tumor in newborns and children. Therefore, it must be first included in the differential diagnosis of abdominal masses. Other oncological diseases, from which CMN should be distinguished in the neonatal period, are different kidney tumors (mainly Wilms), and germ cell ones (GCTs) to which teratomas, yolk sac tumors and choriocarcinomas belong. Indeed, other biochemical markers including serum AFP and beta-HCG should be evaluated [19]; in both reported cases they showed normal results.
Histologically, CMN may be classified into three subtypes: the cellular type is the most common, followed by the classic and mixed ones. The former is the biologically most aggressive and is associated with higher risk of recurrences and metastases [20, 21]. In both our cases, histology was performed to define the diagnosis. From a genetic point of view, 70% of CMNs are characterized by (12;15)(p13;q25) translocation, which causes fusion of the ETS variant 6 (ETV6) and Neurotrophic Receptor Tyrosine Kinase 3 (NTRK3) genes; the oncogene resulting from this translocation, encodes for an oncogenic chimeric protein that would be responsible for tumorigenesis, through dysregulation of NTKR3 signal transduction pathways, and for chemosensitivity of cancer cells [1, 20, 22–24]. The ETV6-NTRK3 gene fusion is also a key marker which allows to distinguish CMN from other renal tumors, as well as the cellular subtype (it is mainly detected in this form [25, 26]) from the other two variants. Such translocation is moreover a prognostic factor associated with higher relapse free-survival (RFS) compared with translocation-negative forms (5-year RFS 100% vs 73%, respectively) [26]; therefore, genetic study may stratify patients with cellular CMNs, identifying those with higher risk of recurrence for which additional chemotherapy treatment might be considered [27]. This rearrangement was identified in both our patients, who did not perform indeed any chemotherapy treatment. It is reported a five-year event-free survival (EFS) rate of 94% and an overall survival (OS) rate of 96% in all CMN cases, with lower expectations for the cellular subtype (85% and 90% of RFS and OS, respectively [6]). Poorer prognoses are associated with chemotherapy toxicity and postoperative complications. Nephrectomy is the treatment of choice; chemotherapy and radiotherapy are rarely required. Critical issues may rise for newborn patients, especially preterm, who require multispecialty co-management of neonatologists, anatomopathologists, pediatric surgeons, oncologists and nephrologists. Actually, in the first patient the clinical instability due to prematurity and to the low birth weight delayed nephrectomy, and the classic CMN diagnosis has been provided through needle biopsy. Conversely, in patient 2 nephrectomy has been soon performed, and histological examination was made after surgical removal of the lesion. In patient 1, the postoperative evolution was complicated by acute abdomen due to bowel occlusion as well as by an enterocutaneous fistula, which required further surgical approaches including the packaging of ileo- and colostomy. A case of ileocolic intussusception is reported in a 6-month-old infant with CMN, who underwent left nephrectomy. Other CMN patients with intestinal occlusion secondary to nephrectomy or with different complications are poorly reported in literature (and synthetized in Table 1), likely due to both the rarity of disease and the low incidence of postoperative issues, especially in otherwise healthy infants [28]. Also, associations with a prevalent side localization have been previously described, but data are conflicting (Table 1).
Table 1
Overview of the previous studies on CMN associated with neonatal/infant complications
References | Diagnosis | Side | Prenatal finding of abdominal mass | Polyhydramnios | Preterm labor (gestational age) | Age at diagnosis | Complications |
Kato H, 2022 [29] | CMN (not specified) | Right | + | + | + 36 WG | preterm newborn (36 WG) | Abdominal compartment syndrome, respiratory distress |
Soyaltın E, 2018 [30] | Cellular CMN | Left | + | - | + 32 WG | preterm newborn (32 WG) | Refractory hypertension |
Kim JS, 2017 [28] | CMN (not specified) | Left | - | not specified | not specified | infant (6-month-old) | Persistent hypertension Right lower quadrant ileocolic intussusception |
Kamaraj S, 2016 [31] | Cellular CMN | Right | - | - | - | term newborn (2-day-old) | Hematuria |
Daskas N, 2002 [32] | Mixed CMN | Right | + | + | + 33 WG | preterm newborn (33 WG) | Hypercalcemia |
Fung TY, 1995 [33] | CMN (not specified) | Left | + | + | - | term newborn (40 WG) | Hypercalcemia, polyuria and polyhydramnios |
Zach TL, 1991 [34] | Mixed CMN | Right | - | + | - | term newborn (38 WG) | Hemorrhagic shock and disseminated intravascular coagulation |
+ = present; - = absent; WG = weeks of gestation |
In patient 2, hypercalcemia and arterial hypertension were observed. In literature, both complications are reported associated with CMN, due to secretion of prostaglandins, parathyroid hormone, parathyroid-related and glucagon-like peptides, as well as renin by tumor cells. Both conditions required medical therapy with furosemide and promptly resolved after tumor removal, highlighting that their pathogenesis is related with factors secreted by tumor cells (paraneoplastic syndromes) [21, 30, 35]. The underlying pathophysiological mechanism of hypertension is the secondary hyperaldosteronism, due to increased plasma renin activity (PRA); therefore, serum electrolytes and acid-base equilibrium (ABE) should be monitored, owing to the higher risk of hypokalemia and metabolic alkalosis [30].
The present study highlights that, although CMN is a usually benign condition, it may be associated with complications in the neonatal period. They may be either post-surgical or systemic-metabolic and require different approaches, also in relation with the potential co-occurrence of prematurity/low birth weight and of their related morbidities. Then, early (already prenatally) multidisciplinary management, as for other congenital diseases [36–40], is essential to offer to patients the most adequate treatment. Actually, the finding of a fetal abdominal mass should prompt suspicion of CMN, especially if it is associated with polyhydramnios, and must alert obstetricians and neonatologists also for the risk of preterm delivery. After birth, multispecialty co-management of newborn patients, which includes the integration of high-level surgical expertise with careful neonatological intensive care [41–46], is necessary to limit and/or prevent complications. Finally, the precise definition of the histopathological and cytogenetic-molecular profiles [47–51] is indispensable to plan an individualized follow-up, oriented to early detection of any possible recurrences or associated anomalies and to improve the quality of life of these children and their families [52–54].