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Cytodifferentiation of a Wilms’ Tumor
Pulmonary Metastasis
Theoretic and Clinical Implications
Thomas A. Seemayer, M.D., F.R.C. Path.1,2
James L. Harper, M.D.2
Derek Shickell, MSc.
Thomas G. Gross, M.D., Ph.D.1,2
Department of Pathology and Microbiology,
University of Nebraska Medical Center, Omaha,
Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska.
Pr. J. Bruce Beckwith contributed significantly
to this article by clarifying the issue regarding
the frequency of this maturation phenomenon,
suggesting mechanisms that might contribute
to this cytodifferentiation, and recommending
that immunohistochemical stains for nuclear
cell proliferation-associated antigens (Ki-67) be
* Derek Shickell is a fourth-year medical student.
Address for reprints: Thomas A. Seemayer,
M.D., F.R.C. Path., Department of Pathology &
Microbiology, University of Nebraska Medical
Center, 600 South 42nd Street, Omaha, NE
Received August 9, 1996; revision received December 6, 1996; accepted December 24, 1996.
BACKGROUND. Complete maturation (cytodifferentiation) of treated metastatic
Wilms’ tumor is an infrequent occurrence. In a large series of reports, Wilms’
metastases have generally contained malignant blastemic elements admixed with
lesser amounts of cytodifferentiated mesenchyme. The authors describe a patient
in whom complete maturation of a pulmonary metastasis was documented after
intensive chemoradiotherapy.
METHODS. A MEDLINE search was employed to identify pertinent cases from 1966
to the present. Key words used in the search included Wilms’ tumor, relapse,
therapy, metastasis, maturation, and cytodifferentiation. Four patients were identified as having completely mature cytodifferentiated pulmonary metastases of
Wilms’ tumor after chemotherapy; one had also undergone irradiation of the pulmonary metastasis.
RESULTS. The primary tumor was an extremely necrotic blastemic Wilms’ tumor
devoid of maturation, as studied after irradiation and chemotherapy. The lung
metastases (examined 13 years later) were represented by a scar and a nodule
comprised of bland epithelium and tubules admixed with mature smooth muscle.
Immunohistochemical stains, used to assess the proliferative rate of these cells,
revealed a nearly negligible proliferation index.
CONCLUSIONS. This report suggests that therapy (chemotherapy and/or irradiation)
may effect, on occasion, complete cytodifferentiation of Wilms’ tumor pulmonary
metastasis. Although this would appear to be an uncommon event, its true incidence is unknown, because few patients with metastatic pulmonary Wilms’ tumor
are subjected to biopsy. The findings of this study suggest that for children with
radiologically stable Wilms’ lung metastases (as determined by imaging studies)
who are yet undergoing intensive chemoradiotherapy, the notion of a surgical
biopsy should be entertained to determine the true nature of the radiologic images.
For some, this might result in the cessation of further therapy that would be
unnecessary and not without complications. Cancer 1997;79:1629–34.
q 1997 American Cancer Society.
KEYWORDS: Wilms’ tumor, cytodifferentiation, chemotherapy, irradiation, metastasis.
n 1927, Cushing and Wolbach coauthored a singular (at the time)
case report describing a 1.5-year-old boy with a paraspinal neuroblastoma that years later matured into a benign ganglioneuroma.1
Because no therapy other than Coley’s toxin was given, they concluded that the tumor had undergone spontaneous maturation. Reports such as this and subsequent experience led Bolande to formulate the concept of ‘‘the oncogenic period of grace,’’ built on the
observation that certain ‘‘malignant’’ pediatric neoplasms tended to
exhibit a benign clinical evolution in very young infants.2 The para-
q 1997 American Cancer Society
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CANCER April 15, 1997 / Volume 79 / Number 8
digm was represented by neuroblastoma Type IV-S,3
which demonstrated a tendency to undergo spontaneous cytodifferentiation and/or necrosis, the latter
leading to tumor regression. Those engaged in the care
of children afflicted with cancer have witnessed this
paradox and recognize that this concept, particularly
in relation to neuroblastoma in infants, is valid.
Recently, two studies described mechanisms that
might be central to this process. In infants, neuroblastoma cells, devoid of a 1p36 deletion and N-myc
oncogene amplification, tend to express high levels of
TRKA, a receptor for neurotrophic nerve growth factor,
and have a near-triploid DNA content. For unknown
reasons, these tumors tend to undergo apoptosis and
regress, independent of therapy.4 In somewhat older
children, Schwann cells are recruited into the tumor
and, through unknown mechanisms, appear to induce
the primitive neuroblastoma cells to differentiate to
mature ganglion cells.5 This latter process probably
explains the findings of the report by Cushing and
Wolbach in 1927.1
Whether drugs and/or irradiation induce cytodifferentiation of a malignant tumor is rarely a subject of clinical discussion despite a substantial body
of experimental work on the biology of cancer
spearheaded by the likes of Dr. G. Barry Pierce over
the past 40 years.6 The data reveal that two pediatric
and one adult malignant neoplasm may, on occasion, be induced to mature with therapy: neuroblastoma, embryonal rhabdomyosarcoma, and testicular teratocarcinoma/embryonal carcinoma. In
the first instance, it is possible that the ingress of
Schwann cells into the neuroblastoma occurs independent of the therapy. The molecular signals that
effect this process, although unknown, are likely
the subject of intense pursuit.5 In the second instance, serial biopsies of urinary bladder and prostatic rhabdomyosarcomas of young children demonstrated progressive cytodifferentiation to mature
skeletal muscle after chemotherapy (unpublished
data). This has been documented by others, particularly when the initial rhabdomyosarcoma was
moderately or well differentiated.7 With regard to
testicular teratocarcinomas and/or embryonal carcinomas, reports over the past 25 years document
complete cytodifferentiation of pulmonary metastases, both with8 and without9 therapy. Thus, therapy designed to ablate rapidly proliferating tumor
clones may allow for the conservation of less proliferative clones of cells capable of further maturation. Moreover, in some instances, this maturation
may be spontaneous, in the absence of therapy. In
contrast to neuroblastoma, spontaneous maturation/regression of Wilms’ tumor have not been described.
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This article presents the case a child who presented with clinical NWTS (National Wilms’ Tumor
Study) Stage IV (pulmonary metastases) Wilms’ tumor
at age 3.5 years. After systemic chemotherapy and irradiation of the abdominal mass, an extensively necrotic
blastemic Wilms’ tumor was removed; she then received cyclic chemotherapy and pulmonary irradiation. At age 16 years, she presented with scoliosis and
was found to have ‘‘new’’ small pulmonary nodules,
which were discovered on magnetic resonance imaging (MRI) of the spine. In comparison, the smaller
of these ‘‘new’’ nodules were not evident in the computed tomography (CT) scan taken 10 years previously. The biopsy findings of several of the larger
nodules, radiologically stable over 10 years, constitutes
the basis of this report.
Case Report
A 3.5-year-old female presented in February 1983 with
a 2-year history of progressive abdominal distention
and a 3-day history of gross hematuria. Apart from a
seizure disorder, she had no relevant past medical or
family history. Physical examination revealed a large
abdominal mass extending from the left diaphragm
into the pelvis. A flat plate radiograph confirmed the
presence of this mass; chest radiographs revealed diffuse, bilateral pulmonary metastases. After informed
consent had been obtained from her guardians, treatment was administered.
Because the tumor was deemed nonresectable,
the patient received abdominal radiotherapy comprised of 3000 centigray (cGy) to the tumor bed using
a 10-megaelectron volt (MeV) Siemens Linear Accelerator (Siemens Medical Systems, Inc., Concord, CA).
The dose was divided into 200 cGy/day, 4 days/week
for a total of 15 fractions. She also received three doses
of intravenous vincristine at 1.4 mg/dose with 5 days
separating each dose.
On March 4, 1983, a left radical nephrectomy was
performed with removal of a necrotic 830-g tumor
(vide infra).
Postoperatively, she received actinomycin D, 240
mg/day, for 5 days and vincristine, 1.3 mg/dose, once
weekly for 6 weeks. On May 11, 1983, total lung irradiation was performed with a cobalt-60 unit. Twelve fractions (75 cGy/fraction) were delivered to the treatment
volume for a total of 900 cGy.
From May 1983 to March 1986, she received cyclic
chemotherapy every 6 weeks comprised of actinomycin D, 275 mg/dose, from Days 1 through 5, and vincristine, 1.1 mg/dose, on Days 1 and 6, alternating
with doxorubicin, 20 mg/m2, on Days 1 through 4. In
March 1985, after reaching the maximal total dose of
300 mg, doxorubicin was discontinued and dacarbazine was started at 3-month intervals at 170 mg/dose
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Wilms’ Tumor Maturation after Therapy/Seemayer et al.
for 5 days. Chemotherapy was discontinued in March
The final sequence of radiotherapy was given to
the lung fields with a 4-MeV Siemens Linear Accelerator in December 1984. Four fractions of 200 cGy were
given for a total dose of 800 cGy.
After completing therapy, the patient was followed
with regular chest radiographs and periodic CT scans
until December 1987. These films continued to demonstrate multiple nodules that had not changed in size
or number. The last radiograph obtained before she
was discharged from follow-up was in April 1992,
which showed neither an increase in size nor in the
number of nodules.
In January 1996, while being evaluated for scoliosis, an MRI of the spine disclosed the presence of previously undocumented lung nodules. A CT chest scan
revealed, in addition to several large, ‘‘radiologically
stable’’ nodules, multiple, small bibasilar pulmonary
nodules not present on a prior CT scan in 1986. She
underwent thoroscopic biopsy of three of these larger
nodules in February 1996 at age 16 years.
After the biopsy report was obtained, the decision
was made to follow the patient with chest CT scans
every 3 months for 1 year and, assuming no change
in the size/number of nodules, to perform CT scans
at 6-month intervals in 1997 and yearly thereafter. At
last follow-up, the most recent CT scan revealed no
change in the remaining nodules when measurements
were made between scans defining the antecedent 6month interval.
FIGURE 1. Photomicrograph of pulmonary tumor showing spindle and
tubular formation (H & E, 1100).
FIGURE 2. Photomicrograph of pulmonary tumor showing triphasic tumor with prominent epithelial component (H & E, 1100).
Three wedge biopsies of lung measuring 2.2 cm 1 1.6
cm 1 0.3 cm, 3.5 cm 1 1.3 cm 1 1.2 cm, and 2.6 cm
1 0.9 cm 1 0.7 cm, respectively, were received. Each
was processed for paraffin embedding by standard
procedures. Hematoxylin and eosin (H & E) 5-mm sections were prepared. Immunohistochemical staining
for muscle specific actin (dilution 1:8000) (Enzo Diagnostics, Inc., New York, NY), desmin (dilution 1:150)
(Dako, Carpenteria, CA), vimentin (dilution 1:25)
(Dako), myoglobin (dilution 1:400) (Dako), MAK-6 keratin cocktail (dilution 1:3) (Zymed, San Francisco, CA),
cytokeratin 7 (dilution 1:400) (Dako) cytokeratin 20
(dilution 1:100) (Dako), epithelial membrane antigen
(EMA) (dilution 1:150) (Dako), AE-1 cytokeratin (dilution 1:100) (Cambridge Research Laboratory, Cambridge, MA), AE-3 cytokeratin (dilution 1:100) (Signet
Laboratories, Dedham, MA), CAM 5.2 cytokeratin (dilution 1:5) (Becton Dickinson, San Jose, CA), and Ki-67
(dilution 1:50) (Dako) was performed using the avidinbiotin-peroxidase technique. To facilitate antigen retrieval for the Ki-67 antibody, the paraffin sections
were immersed in a citrate buffer solution (pH 6.0) at
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90 7C for 30 minutes prior to the application of the
One of the three nodules was found to be a benign
cyst of respiratory origin lined by ciliated respiratory
epithelium. This was judged to be an irrelevant finding. The second was a scar with entrapped ectatic,
mucus-plugged bronchi. The third was comprised of
a benign neoplasm that had infiltrative borders in relation to the lung parenchyma. The neoplasm had three
distinct components: spindle cell, tubular, and epithelial. Glomeruloid structures were not identified (Figs.
1 and 2). The spindle cells were arranged in a fascicular
pattern and featured bland, spindled nuclei and abundant eosinophilic cytoplasm. The tubules were often
clustered and closely opposed to the sheets of epithelial cells. The tubular epithelium was bland and represented by a single layer of cells. The epithelial elements
featured the same nuclear characteristics as the tu-
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CANCER April 15, 1997 / Volume 79 / Number 8
FIGURE 3. Higher power photomicrograph of tumor showing bland epi-
FIGURE 5. Immunohistochemical stain employing antibodies to keratin
thelial and spindle cell nuclei (H & E, 1200).
demonstrating positive staining of both epithelial and tubular elements
(immunoperoxidase stain with antibody MAK-6, 1200).
Immunohistochemical Staining
FIGURE 4. Immunohistochemical stain employing antibodies to muscle
specific actin demonstrating cytoplasmic staining of spindle cell component (immunoperoxidase stain, 1200).
CAM 5.2
CK: cytokeratin; EMA: epithelial membrane antigen.
bules but were arranged in solid sheets. After intensive
examination, mitoses were not observed nor was there
any degree of nuclear pleomorphism or necrosis in
any of these components (Fig. 3).
Multiple sections were next subjected to immunohistochemical studies employing a consortium of antibodies. The spindle cells revealed smooth muscle
qualities by their intense staining with antibodies to
muscle specific actin (Fig. 4), desmin, and, to a lesser
extent, vimentin. The tubules and epithelial components stained, to variable degrees, with antibodies to
various molecular weights of keratin, especially low
molecular weight keratins (Fig. 5) and to EMA. This
immunostaining exposed a distinct difference between the neoplastic tubules and epithelium and those
of the resident epithelial elements of the lung, with
the latter staining more intensely. This was particularly
vivid with antibody CK7, which identifies a cytokeratin
found in normal pulmonary epithelium. Lastly, stain-
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ing for Ki-67, a nuclear cell proliferation-associated
antigen,10 revealed only rare nuclear staining in an
occasional epithelial and tubular cell (õ1:1000 nuclei);
no staining was discerned in the spindle cell populations. The immunohistochemical data are provided in
Table 1.
The antecedent (from 1983) nephrectomy specimen was reviewed. The sections revealed an extensively necrotic cellular tumor infiltrating the renal parenchyma. The monotonous character of the necrotic
tumor cells was consistent with a Wilms’ tumor, blastemic type.
From a MEDLINE search (1966-present), four patients with completely mature Wilms’ tumor pulmonary metastases were identified.11 – 14 In each, the metastasis was predominantly mesenchymal, comprised
of smooth muscle,11 fibrous tissue,13 or mixtures of
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Wilms’ Tumor Maturation after Therapy/Seemayer et al.
fibrous tissue and smooth and skeletal muscle.12,14 In
one, mature ganglion cells were identified.13 Each patient had been treated with chemotherapy; one also
received irradiation to the pulmonary metastases.12
In addition, the MEDLINE search revealed two patients with metastatic (soft tissue and pulmonary)
Wilms’ tumor featuring variable degrees of differentiation. In one patient, a skeletal muscle metastasis was
completely mature, comprised of bland mucinous
glands.15 In another, a solitary lung metastasis was
comprised of benign spindle cells, nerve bundles, adipose tissue, and ganglion cells, albeit admixed with
(presumably malignant) rhabdomyoblasts.16 Both patients had received antecedent therapy.
This case report illustrates the cytodifferentiation of
a Wilms’ tumor pulmonary metastasis into a mature
tumor with bland stromal, tubular, and epithelial elements. From the sequence of events, it appears plausible that therapy (chemotherapy/irradiation, either to
the primary tumor and/or metastases) facilitated this
transformation. Of further interest, a second presumed lung metastasis revealed a scar on histology.
Because pulmonary scars are uncommon in teenagers,
it is possible, albeit speculative, that this represents
fibrous replacement of an antecedent necrotic Wilms’
In recent years, it has been common practice to
irradiate, with or without systemic chemotherapy,
bulky, technically unresectable Wilms’ tumors prior to
their definitive resection. This rationale stems from
the premise that the most immature (blastemic) elements are most likely to be destroyed by the treatment,
thereby allowing for the subsequent surgical removal
of a reduced in size, more surgically amenable, mass.
In a recent report from the National Wilms’ Tumor
Study (NWTS), 83 posttreatment nephrectomy specimens featured extensive tumor necrosis in children
with favorable outcomes.17 The authors noted epithelial, tubular, and mesenchymal differentiation in some
of these tumors (percentage undisclosed). They also
examined 23 posttherapy metastases (lymph node, hepatic, and retroperitoneal, but not pulmonary) and
found õ10% viable tumor in 65% of the metastases;
cytodifferentiation of the metastases was not discussed. A second report from Europe of a series of 61
treated patients with primary Wilms’ tumors describes
skeletal muscle and tubular differentiation in 22 tumors and smooth muscle differentiation in 4 others.
The same authors also noted skeletal muscle differentiation in 6 of 27 untreated Wilms’ tumors.16 This, of
course, raises the question (albeit without resolution)
of whether certain Wilms’ tumors are programmed
genetically to mature. These data suggest that therapy
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not only destroys blastemic elements, but that it facilitates a measure of maturation in Wilms’ tumor, akin
to that described in X-irradiated xenotransplanted
rhabdomyosarcomas.18 Zuppan et al. suggested that
this process might stem from spontaneous maturation
of the more differentiated Wilms’ tumor clones that
survive the brutal ablative therapy directed to the
more proliferative elements.17
Based on their experience and the MEDLINE
search, the authors suggest that the findings presented
in this report, although not rare, are not common
knowledge to most pathologists/pediatric oncologists.
Never having observed this previously, the authors are
only aware of four reports11 – 14 describing ‘‘benign’’
pulmonary metastases in patients with Wilms’ tumor.
Most ‘‘metastases’’ were comprised of benign fibrous
tissue, some with smooth and/or skeletal muscle.
None contained ‘‘benign’’ epithelial tissue or the
abundance of mature tubules as contained in the case
in the current study. Two other cases report extensive
maturation of Wilms’ metastases. One featured mature mucinous glandular elements in a skeletal muscle
metastasis,15 the other described rhabdomyoblastic elements (not illustrated, but presumed malignant) admixed with mature fat, spindle cells, nerve trunks, and
ganglion cells in a lung metastasis.16 The multiplicity
of tissues contained in these articles attests to the
pleuripotent nature of the substrate of Wilms’ tumor,
a fact enunciated by Pr. Pierre Masson in 1938.19
Discussion with experienced pediatric pathologists (with whom this case material has been shared)
led Prs. Bolande and Nezelof to conclude that they had
not previously witnessed such a striking maturational
phenomenon in Wilms’ tumor metastases. Pr. Bolande
was taken with the morphologic similarities between
the pulmonary metastasis and congenital mesoblastic
nephroma (CMN), a tumor he described in 1967.20 He
and others have long ascribed to the view that CMN
represents a cytodifferentiated Wilms’ tumor. Pr. Nezelof stated that colleagues at the French National Cancer Center Institut Gustave-Roussy recall having observed (over many years) two instances of Wilms’ metastases with similar cytodifferentiation (personal
communication). Pr. Beckwith, who reviewed the sections used in the current study drew on the vast wealth
of NWTS material. Although he also interpreted the
sections to represent a cytodifferentiated Wilms’ metastasis, he stated that he has previously witnessed
this degree of maturation after therapy in which the
metastases usually contained mature skeletal muscle;
less often, they contained other bland mesenchymal
elements, including smooth muscle (personal communication). The incidence of such a maturation process has not been established.
The lung biopsy was performed because a current
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CANCER April 15, 1997 / Volume 79 / Number 8
MRI and CT scan disclosed ‘‘new,’’ small nodules not
visualized on the most recent comparison CT scan
performed 10 years previously. The larger, surgically
accessible nodules, radiologically unchanged since
1986, were biopsied. Because the final lung irradiation
was administered in December 1984 and the last cycle
of chemotherapy was completed in March 1986, one
is left to conclude that the metastasis had matured
quite some time earlier. The discovery in 1996 of
‘‘new’’ small nodules is interpreted to reflect enhanced
imaging technology, as disclosed by an MRI and modern vintage CT scanner. The smaller nodules were
likely present in 1986; their size simply precluded detection by the technology of the time.
It would appear evident that therapy of primary
Wilms’ tumor, which is designed to eliminate blastemic elements, also contributes (in some measure) to
variable degrees of maturation of the tumor along epithelial and mesenchymal lines.16,17 The mechanism(s)
responsible for this is (are) unknown. Pr. Beckwith
has suggested two possibilities: the therapy might be
permissive by allowing for the survival of some patients to permit an inherent maturational process to
occur, and, alternatively, the therapy that destroys the
rapidly proliferating elements allows for survival and
differentiation of cells less proliferative and, hence,
more differentiated (personal communication).17
Finally, one posits with what frequency the therapy induces maturation in Wilms’ tumor metastases.
From the review of literature, one is left to conclude
that it is uncommon or, at least, infrequently reported.
The MEDLINE search from 1966 disclosed only a few
cases.11 – 17 However, Pr. Beckwith states that the maturation of Wilms’ metastases is not infrequent (personal
communication). Thus, although the true incidence is
unknown, it may not be as rare as initially presumed.
If so, this has major clinical implications. The modern
management of these children presumes that a lung
radiologic ‘‘image’’ is an explanted malignant clone of
Wilms’ tumor. Because lung biopsies are rarely performed, the child may be subject to additional, possibly unnecessary, therapy. The authors suggest that
children with treated Stage IV Wilms’ tumors who
present with pulmonary (and other) metastases that
remain stable on periodic imaging studies undergo the
minor inconvenience of biopsy to determine the true
nature of these lesions.
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