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Nephrogenic rests: their frequency and their fate.J
Pediatr Hematol Oncol. 2007
Jun;29(6):361-3.
Nephrogenic rests
(NRs) are considered to be precursor lesions of Wilms tumor, the most
common malignant neoplasm of the urinary tract in children. We have
previously reported on 2 cases of NRs, incidentally diagnosed at 2 to
3 months of age during an ultrasound mass screening for urinary tract
malformations between 1992 and 2006. As the screened population
consisted of 17,065 infants, the observed prevalence of NRs in our
area in the examined time period was of 1.17/10,000. This is the first
reliable estimate of the frequency of clinically appreciable NRs in
infants. Microscopic NRs have been found at autopsy in about 1% of
infants. Our data are, therefore, helpful in the assessment of the
proportion of NRs that disappear spontaneously in the childhood age
group. To the best of our knowledge, no false-negative cases were
found. Our observations indicate that our policy of "wait and see" is
appropriate when NRs are identified incidentally during
ultrasonographic screening done for whatever purpose.
Nephrogenic
rests and nephroblastomatosis.
Ann Pathol. 2004 Dec;24 (6):510-5.
The term
nephrogenic rests has been proposed for abnormally persistant foci of
embryonal cells within developmentally normal kidneys. The term
nephroblastomatosis is defined as the presence of diffuse or multiple
nephrogenic rests. Nephrogenic rests represent precursors of
nephroblatoma and they are associated with certain syndromes carrying
a high risk for nephroblastoma. In his classification, Beckwith
describes different types of nephrogenic rests according to
topographic and morphological features. The nephrogenic rests may
undergo regression or proliferation with a high risk for development
of a nephroblatoma.
Nephrogenic
rests mimicking Wilms' tumor on CT.Pediatr
Radiol. 2004 Feb;34(2):152-5. Epub 2003
Oct 7.
Nephrogenic
rests (NR) are persistent benign remnants of embryonic renal tissue. A
small percentage of these may develop into Wilms' tumor (WT).
Radiologic imaging is relied upon to differentiate between these
entities, with the hallmark of malignant transformation being growth
on serial imaging studies. There is, however, considerable overlap in
their imaging characteristics. The authors present a case of two
biopsy-proven NR in a 2-year-old girl with sporadic aniridia that were
indistinguishable from WT on initial radiologic studies. One of the NR
grew on serial imaging studies mimicking a WT, but after resection was
confirmed to be a benign hyperplastic NR on pathologic examination.
Expression of
glial cell line-derived neurotrophic factor and neurturin in mature
kidney, nephrogenic rests, and nephroblastoma: possible role as
differentiating factors.
Pediatr Dev Pathol. 2003
Nov-Dec;6(6):511-9
.
Kidney
development involves a series of complex interactions between the
ureteric bud and undifferentiated mesenchyme, resulting in the
production of the nephron unit. Among locally derived soluble factors,
a particular relevance has been recognized to glial cell line-derived
neurotrophic factor (GDNF) and neurturin (NTN) for the mesenchyme-to-epithelial
conversion of a metanephron. Nephroblastoma is a developmental tumor
of the kidney deriving from metanephric blastema that mimics renal
development and may offer an adequate model of human nephrogenesis. We
investigated the immunohistochemical expression of GDNF, NTN, and
their receptors (GFRalpha1, 2, and 3, and Ret) in normal human kidney
and in 42 nephroblastomas, 20 of which were associated with
nephrogenic rests (group A) and 22 were not (group B). We compared the
immunostaining pattern in group A vs. group B and correlated clinical
course with stage, grade, presence of nephrogenic rests, and
immunohistochemical findings. GDNF, NTN, and their receptors were
expressed in mature kidney and in 67% (GDNF) and 33% (NTN) of tumors,
particularly in the epithelial component; precursor lesions were
negative. No significant differences of expression were observed
between groups A and B tumors. Low stage (P = 0.012), absence of
nephrogenic rests (P = 0.016), intense expression of GDNF (P = 0.034),
and NTN (P = 0.05) were associated with a more favorable outcome.
Besides inductive activity in nephrogenesis, GDNF and NTN may play a
role in maintaining differentiation and survival functions in mature
kidney and may contribute to induce differentiation of nephroblastoma
cells toward the less aggressive epithelial component. The pathway of
activation seems to follow an autocrine/paracrine mechanism, as
neurotrophic factors, GFRalpha1-2-3 receptors and Ret are coexpressed.
Clonality and
loss of heterozygosity of WT genes are early events in the
pathogenesis of nephroblastomas.Hum
Pathol. 2003 Mar;34(3):278-81.
Nephrogenic
rests (NRs), putative precursor lesions of nephroblastomas (Wilms'
tumors), are found in 25% to 40% of kidneys presenting with
nephroblastomas. Nephroblastomas are clonal tumors that, according to
a genetic multistep model, are thought to arise as subclonal
proliferations from NRs by accumulating genetic alterations. Different
candidate genes for the pathogenesis of nephroblastomas have been
identified, including those at chromosomes 11p13 (WT1 gene), 11p15
(WT2 gene), and 16q (WT3 gene). We investigated clonality and loss of
heterozygosity (LOH) at these loci in different subtypes of NR. After
microdissection under microscopic control, we analyzed a highly
polymorphic locus of the human androgen receptor gene (HUMARA) for
nonrandom X-inactivation of genomic DNA using a methylation-sensitive
restriction enzyme to investigate clonality. Out of 14 patients, we
found that 1 case each of adenomatous and hyperplastic NR and 2 of 7
cases of sclerosing NR were monoclonal. Five patients were
noninformative. We assessed LOH at chromosomes 11p13, 11p15, and 16q
by analyzing polymorphic gene loci at these regions. One hyperplastic
NR and the corresponding tumor showed LOH at 11p13 and 11p15; 1
sclerosing NR and the corresponding tumor exhibited LOH at chromosome
16q. We demonstrate for the first time that sclerosing NRs can exhibit
genetic alterations found in nephroblastomas, namely monoclonality and
LOH at the WT gene loci. The histological morphology is no different
between NRs with these genetic alterations and NRs without them. We
conclude that these genetic changes are early events in the multistep
genetic pathogenesis of nephroblastomas; however, they do not seem to
fully determine a malignant potential of NR.
Heterotopic
nephrogenic rests in the colon and multiple congenital anomalies:
possibly related association.Pediatr
Dev Pathol. 2002 Nov-Dec;5(6):587-91.
Heterotopic renal tissue (HRT) in the wall of the colon is a very rare
occurrence, with only five cases published. Our patient is only the
second patient reported to have this abnormality in the absence of
sirenomelia. We describe colonic HRT in a child, associated with
multiple congenital anomalies. The congenital abnormalities were of
the VACTERL type, accompanied by valvular cardiac anomalies that were
clinically diagnosed as Shone syndrome. The HRT was not apparent
clinically or grossly. Microscopically, multifocal islands of renal
tissue consisting of glomeruli, cystically dilated tubules, and
blastema were seen in all layers of the bowel, and simulated "cystic
partially differentiated nephroblastoma." Our case provides further
support to the belief that VACTERL association and sirenomelia
represent related entities.
Incidentally detected nephrogenic rests in the setting of congenital
obstructive uropathy.Can
J Urol. 2002 Aug;9(4):1595-8.
PURPOSE:
Nephrogenic rests (NR) are clusters of cells similar to renal blastema.
NR are frequently seen in kidneys with Wilms' tumor (WT) and are seen
with higher frequency in nephrectomy specimens from obstructed and/or
multicystic dysplastic kidneys (MCDK) compared to autopsy series of
normal kidneys. The significance of NR and their role in tumorigenesis
is largely unknown. We report the findings of two cases with NR
associated with ureteral ectopy/obstruction and review the relevant
literature. MATERIALS AND METHODS: Two cases of upper pole
heminephrectomy associated with ectopic upper pole ureter and
resultant hydronephrosis were found to have nephrogenic rests present
on pathologic examination. A literature search was done to review
recent developments in the understanding of NR and their significance,
primarily to guide patient recommendations regarding follow-up.
RESULTS: Recent developments in the understanding of NR include the
description of intralobar versus perilobar nephrogenic rests and
prognostic considerations associated with each. However, the
implications of finding nephrogenic rests in upper pole hemi-nephrectomy
specimens associated with ureteral ectopy is not well delineated.
CONCLUSIONS: The role of NR in tumorigenesis is still poorly
understood. Because of the still undefined relationship with WT we
recommend patients with incidentally detected NR be followed with
serial abdominal ultrasounds for the first 5 years of life.
Clinicopathologic features of nephrogenic rests and
nephroblastomatosis.
Adv Anat Pathol. 2001 Sep;8(5):276-89.
Nephrogenic
rests are the consequence of residual metanephric tissue in a fully
developed kidney. They usually occur along the perimeter of a mature
renal lobe (i.e., perilobar), within the lobe itself (i.e., intralobar),
or both (i.e., combined). Nephrogenic rests can be grossly obvious or
microscopically discrete. Nephroblastomatosis designates nephrogenic
rests that are multifocal or diffuse, and implies more extensive
disease. Universal (panlobar) nephroblastomatosis denotes complete
replacement of the renal lobe by nephrogenic tissue. The fate of
nephrogenic rests and nephroblastomatosis varies and includes
obsolescence, sclerosis, dormancy, hyperplasia, or neoplasia. Evidence
strongly suggests that neoplastic transformation of nephrogenic rests
results in Wilms' tumor (nephroblastoma). Nephrogenic rests almost
always occur in the setting of Wilms' tumor; perilobar rests show a
strong association with synchronous bilateral Wilms' tumors, whereas
intralobar rests are more strongly associated with metachronous
tumors. Genetic studies have shown that nephrogenic rests often share
many of the same chromosomal defects as Wilms' tumor, which provides
further evidence that they are precursors to nephroblastoma. Thus,
nephrogenic rests are recognized as clinically significant entities
requiring adequate detection and close surveillance. Heightened
awareness regarding the clinical relevance of nephrogenic rests and
nephroblastomatosis (1) has led to improved detection of these
precancerous lesions, (2) fostered more intensive investigation into
their biologic behavior, and (3) initiated in-depth discussions about
potentially new treatment regimens. The pathologists' ability to
identify and detect nephrogenic rests has benefited from the more
efficient Beckwith classification. Radiologists have deployed
high-resolution radiologic/imaging modalities to improve detection of
nephrogenic rests in situ. Clinicians and surgeons are more aware of
the impact that nephrogenic rests have upon patient management.
Despite this progress, more data is needed to further define these
lesions.
Expression of
MIB and BCL-2 in patients with nephrogenic rests with and without
associated Wilms' tumors.Eur
J Pediatr Surg. 2001 Apr;11(2):105-9.
Nephrogenic
rests (NR) are foci of persistent embryonal renal tissue. Because it
has been suggested that NRs are precursor lesions to Wilms' tumor
(WT), they are of considerable clinical interest. NRs vary from
microscopic foci to macroscopic renal tumors, but only a few progress
to WT. In this study, patients with NRs detected during the treatment
of bilateral WT were compared to a group of patients with NRs
incidentally discovered in various clinical settings. Because
mechanisms leading to NR growth and WT formation are poorly
understood, bcl-2 and MIB expression were studied by
immunohistochemistry in both groups. Bcl-2 is an oncoprotein with
inhibitory effects on apoptosis and MIB is a well-established marker
of cell proliferation. Both mechanisms may be of interest for the
growth, regression and transformation of NRs. Intense positive
staining for bcl-2 was found in microscopic NRs. Blastemal cells and
cells with epithelial differentiation were bcl-2-positive. The same
pattern of bcl-2 expression was found in NRs with and without
associated WT. High proliferative activity with intense MIB expression
was found in blastemal areas of WT. Bcl-2 expression in NR is reported
for the first time. Inhibition of apoptosis as a mechanism of NR
formation is suggested. This is of special interest, because bcl-2 is
under transcriptional control of the WT-1 gene.
Proliferation and maturation indices in nephrogenic rests and Wilms
tumor; the emergence of heterogeneity from dormant nodular renal
blastema.Pediatr
Pathol Lab Med. 1995
Mar-Apr;15(2):223-44.
Independent
nephrogenic rests (NRs) accompany many Wilms tumors (WTs), exhibit a
range of qualities suggesting dormancy, maturation, regression, and
hyperplasia, and may carry the WT-1 mutation. We assessed nucleolar
organizer regions, proliferating cell nuclear antigen (PCNA) activity,
cytoplasmic filament expression, and nuclear morphology in 79
nephrogenic rests accompanying 20 WTs. We found a direct relationship
between the size of a blastematous NR and the AgNOR number per nucleus
and a close correlation with PCNA activity. The blastema of most NRs >
1 cm in diameter was indistinguishable from blastema of most WTs. The
smallest NR usually had a low number of silver-reactive nucleolar
organizing regions (AgNORs), low PCNA activity, and absent cytoplasmic
filaments, all characteristics of a nascent dormant state in which
both proliferation rate and protein synthetic activity are low.
Intermediate filament expression was variable in blastema of larger
NRs; cytoplasmic filaments correlated with emergence of epithelial
maturation and absence of filaments with accumulation of immature
cells; mature epithelial structures in NRs had low AgNOR number and
PCNA activity representing a terminal dormant state. The majority of
blastemal cells in most WTs and in one-third of large hyperplastic NRs
lack cytoplasmic filaments. This, plus the occasional finding in large
NRs of features more typical of WTs such as prevalence of apoptosis,
patches of frank necrosis, multinodular architecture, and expanses of
monomorphic, poorly vascularized blastema with low PCNA activity,
suggest that it may be possible to distinguish NRs that are
progressing toward WT from those that are merely hyperplastic. This
study refines the concepts of dormancy and hyperplasia as expressed in
NRs and provides a general framework for probing the relationship of
molecular events to progression of a small proportion of NRs to WT.
Criteria used herein to define dormancy and hyperplasia may be useful
in assessing lesions other than typical WT, such as unusually large or
extensive NRs or uncommon differentiated WTs where the potential for
aggressive behavior may be lower than in usual WTs.
Nephrogenic rests,
nephroblastomatosis, and the pathogenesis of Wilms' tumor.Pediatr
Pathol. 1990;10(1-2):1-36.
A new
classification and terminology is proposed for precursor lesions of
Wilms' tumor (WT), based upon morphology and natural history. The
generic term nephrogenic rest (NR) is used for all WT precursors. Two
major categories of NR are recognized: perilobar (PLNR) and intralobar
(ILNR). Nephroblastomatosis signifies the presence of multiple or
diffuse NRs. Nephroblastomatosis can be classified into four
categories: (a) perilobar (PLNR only); (b) intralobar (ILNR only; (c)
combined (PLNR and ILNR); and (d) universal. The individual rests can
be subdivided into (a) nascent or dormant NRs; (b) maturing or
sclerosing NRs; (c) hyperplastic NRs; and (d) neoplastic NRs. Of 282
evaluable unilateral WT specimens, 28.4% were definitely
rest-positive, and an additional 12.4% were probably positive, with
equal prevalence of PLNRs and ILNRs. Median age at diagnosis of WT was
36 months with PLNRs, 16 months with ILNRs, and 12 months if both
types were present. PLNRs were strongly associated with synchronous
bilateral WTs, and ILNRs with metachronous contralateral WTs. ILNRs
were associated with aniridia and Drash syndrome, whereas PLNRs were
more commonly found with hemihypertrophy and/or Beckwith-Wiedemann
syndrome. The delineation of two distinct categories of WT precursors
suggests pathogenetic heterogeneity for WTs. The biological and
clinical implications of NRs are considered in the context of this
classification.
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