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Wilms' tumor: past, present and (possibly) future.Expert
Rev Anticancer Ther. 2006 Feb;6(2):249-58.
Wilms' tumor
is one of the successes of pediatric oncology, with an overall
cure rate of over 85%, using relatively simple therapies. This
excellent outcome has been the result of collaborative efforts
among surgeons, pediatricians, pathologists and radiation
oncologists. The results that have been achieved in children with
Wilms' tumors support the strong value of the multidisciplinary
team approach to cancer. The two largest cooperative groups that
have studied the optimum treatment for Wilms' tumor are the
National Wilms' Tumor Study group in North America and the
International Society of Pediatric Oncology, involving European
and other countries. The National Wilms' Tumor Study group
recommends primary surgery before any adjuvant treatment, whereas
the International Society of Pediatric Oncology trials are based
on the use of preoperative chemotherapy. The debate on primary
chemotherapy versus primary nephrectomy appears to have been
overcome, in the sense that the advantages and disadvantages of
these two diverse methods have emerged from large and
well-performed clinical trials, and comparably low doses of
anthracyclines and radiotherapy are now used. Challenges remain in
identifying novel molecular, histological and clinical risk
factors for stratification of treatment intensity. This could
allow a safe reduction in therapy for patients known to have an
excellent chance of cure with the current therapy, while
identifying, at diagnosis, the minority of children at risk of
relapse, who will necessitate more aggressive treatments. Another
positive factor is the substantial progress that has been made in
the cure for recurrent patients, with long-term survivals shifting
from 30 to almost 60% in more recently treated patients with
intensive-dose chemotherapy regimens. The combination of lower
relapses and higher salvage rates translated into significantly
improved overall survival for Wilms' tumor patients as a whole.
This review covers current concepts on treatment strategies for
Wilms' tumor, with an overview of the results and achievements of
the important clinical trials.
Nephroblastic
neoplasms.Clin
Lab Med. 2005 Jun;25(2):341-61.
Nephroblastoma, or Wilms tumor, is a malignant embryonal neoplasm
that is derived from nephrogenic blastemal cells, with variable
recapitulation of renal embryogenesis. The pathogenesis of
nephroblastoma is complex and has been linked to alterations of
several genomic loci, including WT1, WT2, FWT1, and FWT2.
Generally, nephroblastoma is composed of variable proportions of
blastema, epithelium, and stroma, each of which may exhibit a wide
spectrum of morphologic variations. Distinguishing nephroblastoma
with favorable histology from tumors that exhibit anaplasia is an
integral component of histologic assessment because of its
prognostic and therapeutic implications. Nephrogenic rests and a
special variant of nephroblastoma, cystic partially differentiated
nephroblastoma, also are discussed.
Metanephric
neoplasms: the hyperdifferentiated, benign end of the Wilms tumor
spectrum?Clin
Lab Med. 2005 Jun;25(2):379-92.
Metanephric
neoplasms represent a spectrum of differentiated lesions that seem
most likely to be related to Wilms tumor. These neoplasms include
a pure stromal lesion, a pure epithelial lesion (MA), and a mixed
epithelial-stromal lesion (MAF). The continuity of these lesions
with Wilms tumor has been demonstrated best in the epithelial
lesions. The relationship of Wilms tumor, MAF with mitoses or
combined MA/Wilms tumor lesions, and usual MAF or usual MA may be
viewed as analogous to that of neuroblastoma, differentiating
neuroblastoma, and ganglioneuroma, in which progressively more
mature or differentiated counterparts of malignant embryonal
lesions are associated with a greater probability of benign
clinical behavior. Such a spectrum already is recognized for
cystic ILNR-derived nephroblastic lesions, ranging from cystic
Wilms tumor, cystic partially differentiated nephroblastoma, and
cystic nephroma. Although this concept implies that the more
active lesions (Wilms tumor) mature with time into inactive ones
(usual MAFs or MA), the converse (that an active Wilms tumor can
arise within an inactive usual MAF or MA) remains possible.
Identical genetic
changes in different histologic components of Wilms' tumors.J
Natl Cancer Inst. 1997 Aug 6;89(15):1148-52.
BACKGROUND:
In young children and infants, Wilms' tumor is the most common
cancer of the kidney. Wilms' tumor exhibits heterogeneous
histopathologic features, consisting of rapidly proliferating
blastemal and epithelial cells and a stromal component that has
heterologous elements (e.g., cartilage, bone, and striated
muscle). It is unclear whether the stromal and heterologous
components of sporadic Wilms' tumor are neoplastic or should be
considered non-neoplastic. PURPOSE: Our purpose was twofold: 1) to
selectively analyze the different histologic tissue components of
sporadic Wilms' tumors, including blastemal, epithelial, stromal,
and heterologous elements, for loss of heterozygosity (LOH) of the
WT1 gene and for expression of the WT1 gene and 2) to determine
the role of WT1 gene expression in the development of these
tissues. METHODS: By use of tissue microdissection techniques,
various histologic elements (blastema, stroma, epithelium, and
striated muscle) of sporadic Wilms' tumor were obtained from
specimens taken from 18 patients. DNA was extracted from the
dissected tissue fragments, and DNA solutions were amplified by
use of the polymerase chain reaction and the polymorphic genomic
markers D11S1392 and D11S904 to detect LOH at the WT1 gene locus
(11p13). Three selected specimens with heterologous elements and
LOH at 11p13 were analyzed for expression of the WT1 gene by means
of the in situ reverse transcription-polymerase chain reaction.
RESULTS: Nine (50%) of the 18 specimens showed LOH at the WT1
locus. Although identical WT1 gene deletion was consistently
observed in all of the various histologic components of these nine
specimens, WT1 gene expression was high in the blastemal and
epithelial elements and low in the stromal and heterologous
elements. CONCLUSIONS AND IMPLICATIONS: Identical allelic deletion
at 11p13 in all components of the sporadic Wilms' tumors examined
suggests that the stromal tissue components are neoplastic rather
than non-neoplastic. In conjunction with variable WT1 gene
expression in the different histologic components, the results
raise the possibility that undifferentiated blastemal cells are
the precursors of the stromal and heterologous elements.
Morphologically benign stromal and heterologous elements may
therefore be derived from neoplastic cells. The developmental
state of the various tissue components of Wilms' tumor may be
attributed to an altered residual WT1 gene that is required for
the maturation of blastemal and epithelial cells but that is not
required for the maturation of stromal and heterologous elements.
Nephroblastomas (Wilms'
tumors) and special variations of nephroblastomas.
Veroff Pathol. 1989;133:1-174.
The results
of the National Wilms' Tumor Study (NWTS) enabled the subdivision
of nephroblastomas into subtypes with "favorable and unfavorable
histology". Nephroblastomas with "unfavorable histology" could be
discriminated by identifying those tumors not responding to
therapeutic regimes proven successful for most cases with
"favorable histology". A major disadvantage of the NWTS
classification has been the exclusion of cytodifferentiated
nephroblastoma variants, which, in contrast to typical
nephroblastomas, can be cured by complete nephrectomy with wide
excision of perinephric soft tissue. In the current study all
types of nephroblastoma and nephroblastoma variants were included
to encompass the whole morphological spectrum which these tumors
may assume. This unselected material is necessary to define the
relation between morphology and prognosis and to compare the
treatment results of various clinical trials. Three hundred and
four cases of nephroblastoma and related neoplasms on file at the
Pediatric Tumor Registry, Kiel, were investigated by conventional
light microscopy, electron microscopy, immunohistochemistry and
DNA-flow cytometry. Of the "typical" nephroblastomas 50% occurred
in the left kidney, 45% in the right kidney, and 5% were
bilateral. Five cases were located in extrarenal sites. There were
121 males and 114 females. The peak incidence was noted in the
third year of life. Of 135 patients 111 are alive and well, nine
are living with disease, and 10 patients have died of disease. The
blastemal predominant and stromal predominant types in our study
were more frequent than in the NWTS. By contrast, the mixed and
epithelial predominant types were more frequent in the NWTS.
Patients with nephroblastomas of mixed or blastemal predominant
type were older than those with epithelial predominant or stromal
predominant type. Electron microscopy showed that nephroblastoma
is derived from metanephric blastema. Blastemal cells are capable
of differentiating into tubular epithelial cells and stromal
cells. Undifferentiated blastemal cells contain exclusively
vimentin intermediate filaments, better differentiated blastemal
cells vimentin and cytokeratin, and stromal cells exclusively
vimentin. Preoperative radio- and/or chemotherapy led to a marked
reduction of undifferentiated blastema and poorly differentiated
tubules, whereas better differentiated tubules, striated muscle,
hyaline cartilage, cells with anaplastic and sarcomatous elements
were not affected. Thus, identification of highly malignant
nephroblastomas with anaplasia and sarcomatous renal tumors was
even possible after preoperative treatment. Congenital mesoblastic
nephroma (CMN; n = 17) is a low-grade malignant,
cytodifferentiated nephroblastoma which very rarely occurs beyond
the fourth month of life and has an excellent prognosis, provided
it has been completely resected
New aspects of
nephroblastoma (Wilms tumor) and other metanephrogenic neoplasms.
Verh Dtsch Ges Pathol. 1989;73:350-71.
We
differentiate (continuing the scheme of the National Wilms' Tumor
Study) three groups of Wilms' tumors (WT), which for practical
reasons also encompass WT variants: 1. a group of low-grade
malignant tumors comprising 9.3% of cases (congenital mesoblastic
nephroma; cystic, partially differentiated nephroblastoma); 2. the
main group of tumors with histologically standard malignancy and
constituting 77.7% of cases, against which a combined therapy is
used depending upon age and stage of spread; and 3. a small group
of tumors of high-grade malignancy (anaplastic WT, clear cell
sarcoma of the kidney; malignant rhabdoid tumor of the kidney).
This latter group constitutes only 13% of cases but is responsible
for a high percentage of total deaths due to WT. To the tumor
group with standard malignancy belong the classic triphasic WT
(without anaplasia) as well as WT "with quantitative deviations",
in which either the blastemic, the epithelial, or the stroma
component dominates. In the differential diagnosis the relatively
frequent blastemic WT must be differentiated from other so-called
small, round, and blue cell tumors of childhood, especially the
undifferentiated neuroblastomas. Pseudo-rosettes and cytokeratin
expression are signs of an "early" epithelial differentiation.
Anaplastic WT (comprising 6.1% of our cases) are diagnosed
according to the criteria of BECKWITH and PALMER (1978). They are
aneuploid tumors and occur predominantly in children over two
years of age. By contrast, the histogenetic still undefined clear
cell sarcomas and malignant rhabdoid tumors of the kidney occur
chiefly in children under two. Both tumors are diploid,
notwithstanding their high-grade malignancy. Clear cell sarcoma,
which contains a high content of vessels and comprises 3.7% of our
cases, consists of cells with weakly stained and partially
vacuolized cytoplasm. In contrast to normal WT, clear cell sarcoma
often progresses to bone metastases. Malignant rhabdoid tumor
(2.7% of our cases) possesses cells with large, roundish nuclei,
pale chromatin, very prominent nucleoli and characteristic
spherical intermediate filament condensations. Cross striation and
myoglobin are never present. Malignant rhabdoid tumor is not a
genuine kidney tumor; it may also occur extrarenally. Low-grade
congenital mesoblastic nephroma is a spindle cell tumor often
exhibiting high cellularity and characterized by fingerlike
projections extending into the adjacent kidney tissue.
Nephroblastomatosis, with preferential perilobular localization,
is a potential WT precursor found in 25% to 40% of all nephrectomy
specimens containing WT and in all cases of bilateral and
multifocal WT. Nevertheless, only a small proportion of the
usually very small "nephrogenic remnants" lead by way of an
adenomatous proliferation to manifestation of WT.
Clinicopathologic features and prognosis for Wilms' tumor patients
with metastases at diagnosis. Cancer.1986 Dec
1;58(11):2501-11.
Comparisons were made between 236 Wilms' tumor patients with
metastasis to the lungs and/or liver at initial diagnosis who were
registered on the National Wilms' Tumor Study (NWTS) during 1969
to 1983, and 1755 patients who did not have overt metastases at
diagnosis. Patients with evidence of regional spread of disease
beyond the kidney, especially if to the renal vein or lymph nodes,
were much more likely to have overt metastases present at
diagnosis than those with apparently localized disease. The
presence of metastases was also correlated with age at diagnosis,
ranging from 1% among infants younger than 1 year of age to 24%
for those aged 6 years or older. The percentage of tumor deaths
for patients with metastases at diagnosis (Stage IV) and a primary
tumor of favorable histology (FH) declined from 29% at 2 years
postdiagnosis on the first therapeutic trial (NWTS-1) to 9% for
the most recent one (NWTS-3), and is now comparable to that for
patients without metastases but with nonresectable local invasion
at diagnosis (Stage III). The local extent of disease also
influenced the survival outcome for Stage IV/FH patients. Survival
was poor for those with anaplastic or sarcomatous (unfavorable)
histology, regardless of local staging or trial. There was no
difference in survival according to metastatic site (liver +/-
lung vs. lung only) if present prior to treatment. By contrast,
patients who developed liver metastases during or after treatment
had an especially poor chance for survival as compared with those
who developed lung deposits at those times.
Anaplastic Wilms'
tumor: clinical and pathologic studies.J
Clin Oncol. 1985 Apr;3(4):513-20.
A review of
almost 1,200 children participating in the first and second
National Wilms' Tumor Study (NWTS-1 and -2) has demonstrated a
number of significant differences in the clinical presentation and
response to therapy of anaplastic and nonanaplastic Wilms' tumor.
Compared to their counterparts, children with anaplastic Wilms'
tumor were generally one to two years older at diagnosis, more
were non-white, and more had lymph node metastases at diagnosis.
Consistent with previous studies, children with anaplastic Wilms'
tumor survived for a significantly shorter time than those with
non-anaplastic Wilms' tumor. A hopeful outlook, however, was
suggested by the NWTS-2 experience since the more aggressive
chemotherapies used in this study appear to have substantially
improved the survival of patients with diffusely anaplastic
tumors. Also, the survival of NWTS-2 patients with anaplastic
Wilms' tumor was determined in part by clinicopathologic stage. It
may be possible therefore to refine therapy according to stage so
as to provide children with localized disease a chance for cure
with fewer untoward treatment-related sequelae.
Wilms' tumor and
other renal tumors of childhood: a selective review from the
National Wilms' Tumor Study Pathology Center.Hum
Pathol. 1983 Jun;14(6):481-92.
Selected
studies of Wilms' tumor and related renal neoplasms in children,
which have been based on the National Wilms' Tumor Study Pathology
Center collection of more than 2,600 renal tumors of childhood,
are reviewed. The purpose of the review is to illustrate the value
of the collaborative approach to uncommon pathologic specimens and
to distinguish several tumors often confused with Wilms' tumor,
including renal adenocarcinoma, renal teratoma, and renal
neurogenic tumors. The unfavorable prognostic significance of
anaplastic cells in Wilms' tumor is emphasized. Two recently
described clinicopathologic entities--clear cell sarcoma of kidney
and malignant rhabdoid tumor of kidney--and morphologic variants
often confused with Wilms' tumor or congenital mesoblastic
nephroma of infancy are discussed. Clear cell sarcoma of kidney
and malignant rhabdoid tumor of kidney are, apparently,
distinctive neoplasms, not Wilms' tumor variants.
Histology and
prognosis of nephroblastoma--with special reference to special
variants. Klin
Padiatr. 1983 May-Jun;195(3):214-21.
101 cases of
Wilms' tumor (nephroblastoma) were investigated by light
microscopy. In 80 cases a diagnosis of triphasic nephroblastoma
was made. 21 cases were classified as special variants of Wilms'
tumor. These included congenital mesoblastic nephroma (n = 5),
fetal rhabdomyomatous nephroblastoma (n = 2), cystic partially
differentiated nephroblastoma (n = 3), nephroblastoma with focal
or diffuse anaplasia (n = 2), clear cell sarcoma or bone
metastasizing renal tumor of childhood (n = 4), rhabdoid tumor (n
= 2) and rhabdomyosarcomatous nephroblastoma (n = 3). Based on our
own follow-up data and on information from the literature we
propose to separate the group of nephroblastomas into three
categories of different prognosis: 1. Nephroblastomas of low risk
(congenital mesoblastic nephroma, fetal rhabdomyomatous
nephroblastoma, cystic partially differentiated nephroblastoma) -
in most of these cases simple nephrectomy sufficient as adequate
therapy. 2. Nephroblastomas of standard risk (triphasic
nephroblastomas) - therapy according to stage of disease. 3.
Nephroblastomas of high risk (nephroblastomas with focal or
diffuse anaplasia, clear cell sarcoma, rhabdoid tumor,
rhabdomyosarcomatous nephroblastoma) - successful therapy has as
yet to be developed.
Histopathology and
prognosis of Wilms tumors: results from the First National Wilms'
Tumor Study.Cancer.1978 May;41(5):1937-48
Detailed
histological analysis of 427 cases entered on the first National
Wilms' Tumor Study revealed that lesions with foci of marked
cytological atypism (anaplasia), and those composed predominantly
of sarcomatous stroma, were associated with unfavorable outcome.
Twenty-five patients had anaplasia, and 24 had sarcomatous lesions
of which a total of 28 (57.1%) died of tumor. Three hundred and
seventy-eight patients had tumors which showed neither of these
features, and only 26 (6.9%) died of tumor. Seven of ten deaths
due to tumor in patients diagnosed before two years of age were
associated with sarcomatous lesions. Three sarcomatous patterns
were recognized, of which one, designated "clear cell" sarcoma,
had a predilection for bony metastases. Using criteria defined and
illustrated in this paper it is possible to identify in advance
those patients likely to do poorly using current therapeutic
approaches.
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