Extrarenal nephroblastomatosis in children: a report of two cases

Extrarenal nephroblastomatosis, also called ectopic immature renal tissue (EIRT) [1‐3], extrarenal nephrogenic rest (ENR) [4, 5], hamartoma with primitive renal tissue [4] and mesonephric remnant tissue [2], has been reported only rarely in the world literature. This unusual lesion is often associated with extrarenal Wilms tumor. However, the mechanism underlying the development and persistence of extrarenal nephrogenic rests remains unclear.

We retrospectively reviewed our hospital records of the past 10 years for cases of nephroblastomatosis and nephroblastoma (Wilms tumor), and identified only two cases of extrarenal nephroblastomatosis, one in the inguinal canal and the other in the vertebral canal. Here, we describe the clinical characteristics, diagnosis, treatment and embryological implications in these two cases.

Kidney development, which is also called nephrogenesis, is a complex process involving tissues with two distinct embryological origins: nephrogenic and ductogenic [6]. Nephrogenic tissue develops from the intermediate mesoderm and proceeds through a series of three successive phases: pronephros, mesonephros and metanephros. This process normally ceases after 36 weeks of gestation, at which time, the metanephric blastema in the kidney disappears [7]. Occasionally, the nephrogenic blastema fails to mature into normal renal parenchyma, and the persistent blastemal tissue is then referred to as nephrogenic rests, which may undergo oncogenic mutation to form a malignant embryonal tumor known as nephroblastoma. On histological examination, nephrogenic rests usually appear as aggregates of abnormally persistent embryonal nephroblastic tissue with small clusters of blastemal cells, tubules and occasional glomeruli, with a variable amount of admixed fibrous stroma. Nephrogenic rests can be unifocal, multifocal or diffuse. The term nephroblastomatosis is used to refer to diffuse or multifocal nephrogenic rests or their derivatives [8]. Nephrogenic rests can be subclassified into perilobar nephrogenic rests and intralobar nephrogenic rests, according to their location in relation to the renal lobe on histological examination. Occasionally, nephrogenic rests are found in ectopic sites, such as the inguinal canal [5], lumbosacral area [3, 9‐12], adrenal gland [13], thorax [14, 15], colon [16] and heart [17]. There are two possible distinct fates for nephrogenic rests: to be an isolated developmental abnormality, or the early stage of a neoplastic process, with the latter being more clinically significant. Most nephrogenic rests become dormant, mature or spontaneously regress. Some undergo hyperplastic overgrowth, which is hypothesized to be an intermediate, pre-neoplastic stage in the process of tumorigenesis. Only a small number undergo a neoplastic induction to transform into Wilms tumor, which is the most common malignant renal neoplasm in children [18].

Differential diagnosis between extrarenal nephroblastomatosis and extrarenal nephroblastoma is mandatory when ectopic immature renal tissue is found. Sometimes it is difficult to distinguish ectopic nephrogenic rests from Wilms tumor on histology, and it is especially difficult to distinguish between a proliferative nephrogenic rest and a small Wilms tumor [19]. Generally, nephroblastoma tends to form round nodules enclosed in a fibrous pseudocapsule owing to its rapidly expansile growth. On histological examination, the lesion comprises nephrogenic tissues, such as blastemal, epithelial (tubular and glomeruloid) and mesenchymal elements. The distinguishing characteristic of nephroblastoma is frank atypia including disordered structures, atypical mitoses and marked pleomorphism. Otherwise, approximately 5% of Wilms tumors show anaplastic cells, which is a typical characteristic of malignant, indicating poor prognosis [20, 21]. In contrast, the lesion in nephroblastomatosis usually consists of small multiple microscopic nests and islets. Mitoses are usually sparse, except in proliferative nodules, which exhibit high mitotic rates and moderate pleomorphism, but no obvious atypia. Proliferative nephrogenic rests invariably show striking enlargement, but lack the peritumoral pseudocapsule characteristic of Wilms tumor.

In both our patients, the possible differential diagnoses included teratoma, a neoplasm originating from testicular tissue, metastasis and malignancies other than Wilms tumor. The nephrogenic epithelial elements (glomeruli, tubules) in the two cases had differentiated to a rather advanced degree, and rare mitoses with no atypia were found scattered within the dense fibrous tissue, indicating a benign neoplasm. The diagnosis of teratoma was excluded due to the lack of other teratomatous non-nephrogenic tissues.

The ectopic nephrogenic rests were thought to have originated from mesonephric or metanephric tissue. In the few published studies on this topic, ectopic nephrogenic rests have been reported predominantly in the retroperitoneum and inguinal region [22]. In our first patient, the mass was attached to the testis, which is consistent with an nephrogenic rest arising from mesonephric tissue, because the mesonephros is associated with the developing gonad, embryologically [23]. There have also been several case reports of intraspinal nephrogenic rests located in the lumbosacral area and frequently associated with spinal dysraphism [3, 10]. This peculiar association of spinal abnormalities with nephrogenic rests in the lumbosacral region, where the metanephros comes closest to the spinal cord [24], supports the hypothesis that neural tube abnormalities interfere with the migration of renal tissue and thereby result in ectopic nephrogenic rests [4, 12]. However, in our second patient, the lesion was located in the lower thoracic region, indicating that nephrogenic remnants may be trapped between the dura and the developing spinal cord early during nephrogenesis.

From the scarce literature available on this subject, we conclude that most nephrogenic rests can be expected to remain subclinical, and thus, complete excision of the lesion with conservative treatment is recommended. However, it is reported that approximately 40% Wilms tumors were associated with nephrogenic rests [19]. Owing to the close association between renal nephrogenic rests and Wilms tumor, regular follow-up is required for such lesions until the period of risk has ended. This ensures the detection of malignant transformation at an early stage [25, 26].

Written informed consent was obtained from the patient’s parents for publication of this case report and any accompanying images. A copy of the written consents is available for review by the Editor of this journal.