HISTOPATHOLOGY AND PROGNOSIS OF WILMS

TUMOR
Results from the First National Wilms’ Tumor Study
J. B. BECKWITH,MD, ANDN.F. PALMER,
MB, BS

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.
Cancer 41:1937-1948, 1978.

W ILMS’ TUMOR PRESENTS A COMPLEX PROB- geneity, has been the rarity of this tumor. Pre-
lem for the histopathologist attempting vious studies have been based upon relatively
to correlate structure with natural history, be- small numbers of cases, usually spanning many
cause of its diversity of cell types, tissue patterns, decades, during which time therapy has been in
and degrees of differentiation. Several attempts continuous evolution and dramatic improve-
to relate histopathology to prognosis of Wilms’ ment in survival rates has been occurring.
tumor have been r e p ~ r t e d ~ , ~ , ~but ’ ~ , ~ ~ ~T~h~e N a t i o n a l W i l m s ’ T u m o r S t u d y
, ” ,none
has yet achieved general acceptance. .4 major (NWTS)5,8,’begun in 1969, has accumulated a
problem, in addition to its structural hetero- large number of patients, each staged by stan-
dardized criteria and treated uniformly accord-
ing to a small number of therapeutic protocols.
From the Departments of Pathology and Pediatrics, Uni- Adherence to these protocols has been closely
versity of Washington, School of Xledicine and the Depart- monitored and has proved to be of high order.
ment of Laboratories, Children’s Orthopedic Hospital and This study, therefore, presents a unique oppor-
k4edical Center, Seattle, Washington. tunity for the correlation of histopathology of
Address for reprints: J. B. Beckwith, M.D., Children’s
Orthopedic Hospital and Medical Center, P. 0 . Box 5371,
Wilms’ tumor with therapeutic response.
Seattle, Washington 98105. It is the responsibility of the Pathology Center
Supported by Grant CA-11722 from the U. S. National of the NWTS to collate, analyze, and report
1nstitutes of Health. Principal investigators enrolled in the upon the pathological data accrued during the
three participating cooperative study groups, Cancer and study. O n e aspect of this activity, the derivation
Acute Ixukrmia Group B., Children’s Cancer Study Group,
and Southwest Oncology Group also received support from of a histopathological classification system of
the NIH. prognostic significance, forms the basis of this
The authors gratefully acknowledge the contributions of report.
the many surgeons, pediatricians, and radiation therapists
treating the patients included in this study, and in particular
the patholo3ists who kindly submitted the necessary sections
and reports without which this study would have been im- MATERIALS
A N D METHODS
possible. The National Wilms’ Tumor Study Committee
(G. J . D’Angio, X4.D.. A. E. Evans, hl.D., PJ. Breslow, Detailed descriptions of NWTS objectives, eli-
ph.D., H. C. Bishop, kf.D., W . E. Goodwin, M.D., L. L. gibility criteria, data sources, and initial treat-
Leape, M.D., L.. F. Sinks, M U . , W. W. Sutow, M.D., ment results have appeared elsewhere.*,’ T h e
M. Tefft, M.D., and J . A . Wolff, M . D . ) contributed ma- treatment schema and NWTS grouping criteria
terially to many aspects of this study, as did the staff of
the NWTS Data and Statistical Center. are reproduced in Table 1 as an aid to inter-
Accepted for publication December 23, 1977. pretation of the results of this study.

0008-543X-78-0500-1937-0115 @ American Cancer Society

1937
1938 May 1978
CANCER
1. Grouping Definitions and Initial Therapeutic Regimens Used in NWTS 1’
TABLE
Group Definition
I Tumor limited to kidney and completely resected
11 Tumor extends beyonds kidney and completely
resected
111. Residual nonhematogenous tumor confined to
abdomen
IV. Hematogenous metastases
.i\bbreviations: R T = radiotherapy; AMD = Actinomycin D ; VCR
Study Population
The present paper is based upon the first
NWTS (NWTS I ) which was terminated in De-
cember 1974. NWTS 11, which is still in prog-
ress, utilizes differing therapeutic protocols, and
at present includes only a small number of pa-
tients for whom a full two years of followup
information is available. Three hundred and
fifty-nine randomized and 171 nonrandomized
patients with Wilms’ tumor were entered onto
the NWTS I study regimens. From this group of
530 patients, adequate histological materials, as
defined below, were available from 477. This
population was reduced to 427 by excluding 12
cases whose first “relapse” occurred in the con-
tralateral kidney, 2 with multicentric tumors of
widely differing histopathology in the resected
kidney, 15 assigned to the Group IV B treatment
regimen which included preoperative vincristine
which might confound histological appearances,
4 with “cellular mesoblastic nephromas,” as de-
scribed below, and 17 patients for whom fol-
lowup information of at least two years duration
was unavailable. Sixteen of these 427 died with-
out demonstrated tumor relapse and were sepa-
rately considered in most of the analyses. It
should be noted that there are minor differences
in numbers of cases in a companion paper upon
this same p ~ p u l a t i o nsince
, ~ differing criteria for
exclusion were utilized in the two studies.
Patients who relapsed on NWTS I were sub-
sequently treated nonuniformly. In this study,
outcome data are presented according to the
original treatment regimen. No attempt was
made to determine which form of subsequent
treatment produced the best patient retrieval.
End points for analysis were tumor relapse
and death due to tumor. T h e former was defined
as the first clinical determination of recurrent or
metastatic tumor, and for Group IV patients as
recurrence of tumor at sites of previously treated
metastasis, or the appearance of new metastatic
Vol. 41
~ ~ ~~~
Initial Therapeutic Regimens
A. Nephrectomy + R T + AMD
B. Nephrectomy + AMD. No RT.
A. Nephrectomy + R T + AMD
B. Nephrectomy + R T + VCR
C. Nephrectomy + R T + AMD + VCR
A. Surgery + R T + AMD + VCR
B. Preop VCR + Surgery + R T + AMD + VCR
= Vincristine.
lesions. Death due to tumor was defined as pa-
tients dying with clinical and/or necropsy evi-
dence of tumor persistence at the time of death.
Eight patients with persistent tumor two
years after nephrectomy are included among the
survivors in this study. Since 92% of deaths due
to tumor in NWTS I occurred within two years
of nephrectomy, two-year survival seems a rea-
sonable approximation of total survival. If some
or all of the patients now surviving with persist-
ent tumor subsequently die of tumor, the mor-
tality rates reported below will not be drastically
altered.
Histological Examination
Histological materials were considered in-
adequate when section quality was insufficient
to permit cytological evaluation, or when at least
one square centimeter of viable tumor tissue was
not available in the microscopic sections. Four
or more sections of viable tumor were available
from 75% of the study cases.
Any tumor was accepted as a Wilms’ tumor
which corresponded to the definition given pre-
viously by one of the investigators.
All histological data were generated by one of
us UBB) without knowledge of outcome or other
details of the cases. All terms recorded on the
data sheets were defined in advance of the speci-
men review. T h e presence or absence of 30 tissue
patterns or cell types was recorded for each tu-
mor. T e n of these were blastemal patterns, 10
epithelial, and 10 were stromal. T h e epithelial
and stromal elements were also subdivided into
“differentiated” and “undifferentiated” cate-
gories, also using previously defined criteria. For
example, tubules were scored as “differenti-
ated” if columnar or cuboidal cells surrounded a
lumen, and as “undifferentiated” if no lumen
was present. Occasional difficulty was experi-
enced in assignment of closely packed, spindle
shaped cells into blastema or into undifferenti-
ated stroma. T h e arbitrary criterion used here
No. 5 WILMS’TUMOR Beckwith and Palmer 1939

was that if the ratio of length to diameter of the
nucleus was over 3 to 1, the cell was classified as
stroma, otherwise it was recorded as blastemal.
In addition to cataloguing the elements pres-
ent within the available sections of each tumor,
an estimate was made of the proportion of viable
tumor composed of epithelium, blastema, and
stroma respectively. If any one of the 30 patterns
or cell types mentioned above comprised more
than 65% of the sectioned tumor surface, that
pattern name became the “subtype” designa-
tion for the specimen, and the category under
which that subtype fell became the “type” des-
ignation. For example, a tumor estimated to be
composed of 75% differentiated tubules, 5% un-
differentiated tubules, 10% diffuse blastema and
10% differentiated fibromyxoid stroma would be
of “tubular differentiated” subtype, and “epi-
thelial” type. If no one cellular element or tissue
pattern predominated to this extent, ihe term
“mixed” was applied.
Finally, the presence or absence of cellular
atypism was recorded for each specimen Only
florid examples of atypism were recognized,
since the defining criteria for this designation
required that all three of the following condi-
tions be satisfied: 1) cells were present with a
nuclear diameter at least three times that of
adjacent nuclei of the same cell type, 2 ) these
cells had marked hyperchromatism indicative of
increased chromosome numbers, and 3 ) abnor-
mal mitotic figures (excluding simple metaphase
arrest) were present. Atypia thus defined was
given the convenient shorthand term ranaplasta,
though we recognize that this term has been
used in several differing ways since Hanse-
mann” applied it to tumors with nuclear en-
largement and pleomorphism that he attributed
to aneuploidy and polyploidy. Anaplasia was
scored as “focal” when found in fewer than 10%
of microscopic fields examined at high dry mag-
nification, and as “diffuse” when present in
more than 10% of such fields.
RESULTS
Table 2 presents, in abbreviated form, the
outcomes for the major tumor types encountered
in this study. For most subtypes the number of
specimens was too small for adequate analysis,
so outcome data in this paper relate only to
major histological types. This aspect will be re-
ported upon in more detail when sufficient case
material has been accrued in the NWTS. With
the exception of the stromal predominant lesions
described below, there was no powerful effect of
tumor type upon outcome. It is, however, of
interest that nonanaplastic tumors composed
predominantly of blastema fared no worse than
predominantly epithelial or mixed tumor types
which are presumably more highly differenti-
ated. I t is also worthy of note that tumors com-
posed primarily of differentiated tubules tended
to occur in younger patients. 51.3% of non-
anaplastic differentiated epithelial tumors oc-
curred in patients under two years of age; while
only 31.2 percent of all patients fell into this age
category (xz= 10.2, p < 0.002).
T h e most conspicuous outcome of this study
was the demonstration that anaplasia, as de-
fined above, and sarcomatous Wilms’ tumors,

TABLE
2. Relationship of Histological Type to Clinical Outcome and Age at Diagnosis

Under T w o Years at Diagnosis Over T w o Years at Diagnosis

Relapse Tumor Non Tumor Relapse Tumor Non Tumor
Histological Type Total Free Death Death Total Free Death Death

Mixed
No anaplasia 72 69 160 116 13 10
Focal anaplasia 1 1 13 7 5 0
Diffuse - - 6 1 4 0
Epithelial Predominant
No anaplasia 24 24 25 19 2 0
Diffuse anaplasia - - - 0 1 0
Blastemal Predominant
No anaplasia 15 13 80 62 8 2
Focal anaplasia - - 1 0 1 0
Diffuse anaplasia - - 3 0 3 0
Stromal Predominant
Non sarcoma* 2 2 - - - -
Sarcoma 8 0 16 5 7 2

* T w o tumors with predominantly skeletal muscle differentiation. “Cellular mesoblastic nephromas” do not appear
in this table (see text).
1940 CANCER
May 1978 Vol. 41

TABLE
3. Major Histological Categories in Relation to Therapeutic Regimen Assigned,
Age at Diagnosis, and Clinical Outcome

Clinical Group and Treatment Regimen

No Anaplasia
(under Two Years) IA IR 11-IIIA 11-IIIB 11-IIIC IVA Total
Total 33 39 12 8 20 1 113
Relapse-free 31 38 12 8 18 1 108
Tumor death 1 1 0 0 1 0 3
Son-tumor death 0 1 1 0 0 0 2

S o Anaplasia
(Over Two Years)
Total 39 36 40 27 81 42 265
Relapse free 30 23 24 19 69 32 197
Tumor death 0 3 6 1 6 7 23
Non-tumor death 1 1 1 1 2 6 12

Anaplasia
(All Ages)
Total 4 2 7 2 8 2 25
Relapse free 3 1 1 0 4 0 9
Tumor death 1 0 5 2 4 2 14
Son-tumor death 0 0 0 0 0 0 0

Sarcoma
(All Ages)
Total 2 1 7 5 9 -l 24
Relapse frer 2 0 0 0 3 0 5
Tumor death 0 0 4 5 5 0 14
Non-tumor death 0 1 1 0 0 0 2
-

composed chiefly or exclusively of poorly differ- over two years of age at diagnosis, 16 (66.7%)
entiated stromal cells, contributed heavily to re- relapsed and 14 (58.3%)died of tumor.
lapse rates, and especially to tumor death rates. The extent of this change was of some signifi-
The remainder of this section will concentrate cance. T h e relapse and tumor death rates were
upon this aspect. higher when anaplasia was “diffuse” than when
it was “focal” (Table 4) but small numbers
Ana plasia preclude final conclusions from this comparison,
and any degree of anaplasia in the primary tu-
The presence of large, pleomorphic, hyper- mor markedly worsened the outcome.
chromatic tumor cell nuclei with abnormal There is no strong correlation between pres-
multipolar mitotic figures was an unfavorable ence of anaplasia and extent of tumor at diagno-
prognostic factor, as is shown in Tables 3 and 4. sis, though only 6 of 25 anaplastic lesions were
This cytological feature was apparently influ- in clinical Group I, limited to the kidney (Table
enced by age, as only 1 of 25 cases with ana- 3).
plasia was younger than two years (Table 2), Anaplasia occurred among the epithelial,
and in this case the change was focal and not stromal, or blastemal populations of Wilms’ tu-
associated with relapse. Among the 24 cases mor, and many tumors showed this change si-
multaneously in all three cell types. Usually the
stromal compartment had the most extreme de-
TABLE
4. Significance of Anaplasia in NWTS I.* gree of cellular atypia. Typical illustrations of
Degree of No. Survivors Relapse Free
anaplasia are shown in Figures 1-4. This change
Anaplasia Cases No. % No. % as we have defined it is easily recognized in most
instances, and usually is detectable using the
Absent 364 338 92.9 305 88.8 scanning lens of the microscope, due to the gi-
Focal 15 9 60.0 8 53.3 gantic, hyperchromatic nuclei that are the hall-
Diffuse 10 2 20.0 1 10.0
mark of anaplasia. There are several potential
* This table excludes the 24 sarcomatous cases, and also sources of error that could lead to false identifi-
14 non sarcomatous cases dying without evidence of tumor. cation of anaplasia, some of which require ex-
No. 5 WILMS'TUMOR Beckwith and Palmer 1941

F I ~ . 1. A n a p l a s t i c
cells among a mixed pop-
ulation of hlastemal a n d
strornal elements. with
predominant in-
volvement of the latter
( H & E X200).

amination under high magnification [or con-
firmation :
1. Fused or smudged masses of nuclear
chromatin due to technical artifact.
2. Overlapping cells in thick sections.
3. Circulating megakaryocytes within the
tumor vessels.
4. Calcification.
5. Moderate cellular enlargement related
to differentiation of a tumor cell popu-
lation. This is most commonly seen
when blastemal foci are evolving toward
epithelial cells. However, this phenome-
non does not meet the three criteria
given earlier for anaplasia, namely a
threefold increase in nuclear diameter
plus definite nuclear hyperchromatism
and bizarre mototic figures.
6. Cellular atypia resulting from irradia-
tion or chemotherapy. Since previously
treated tumors were excluded from this
study, we cannot evaluate the signifi-
cance of cellular atypism in such speci-
mens.

FIG. 2. High power

magnification of large,
bizarre, hyperchromatic
cells typical of anaplasia
( H & E X625).
1942 CANCERMay 1978
Anaplastic Wilms’ tumors treated with com-
bination chemotherapy (Groups 11-IIIC) fared
better than those treated with a single agent
(Groups 11-111 A and B). Eight of 9 patients in
Groups I1 and I11 given single agent therapy
relapsed and 7 died of tumor (Table 3 ) . Four of
8 .patients given double agent therapy relapsed
and died of tumor.
Sarcomatous Wilms’ Tumors
Twenty-four specimens encountered during
the course of this study were composed either
Val. 41
FIG. 3. Anaplastic
cells p r ed o mi n an t l y
within a blastemal popu-
lation, with an abnormal
polyploid mitotic figure
near center (H & E
x 200).
predominantly or exclusively of poorly differen-
tiated stromal cells which were difficult to iden-
tify with certainty. Their constituent cells were
larger than those of blastema, and possessed
more abundant cytoplasm. Most of these speci-
mens exhibit one or more of three distinct pat-
terns. The terms used for these patterns are
purely descriptive, and subject to change when
ultrastructural and other studies identify their
nature. A paper presenting these sarcomatous
lesions in greater detail is in preparation.
Rhabdomyosarcomatoid pattern: This pattern, de-
FIG. 4. Several ana-
plastic cells within a pre-
dominantly epithelial le-
sion (H & E X200).
No. 5 WiLMs’ TUMOR Beckwith and Palmer
9 1943

FIG. 5. “Khabdomyo-
sarcomatoid” pattern
with diffuse sheet of
polygonal cells, most of
which have abundant
acidophilic cytoplasm
( H & E X200).

picted in Figures 5 and 6, predominated in 8
specimens. It is composed of sheets of polygonal
cells with abundant acidophilic cytoplasm and
rounded, vesicular nuclei usually possessing a
very prominent centrally located hematoxy-
philic nucleolus. Sometimes these cells aggre-
gate into epithelioid or alveolar arrangements.
Variable numbers of cells contain large, spheri-
cal, rounded hyaline cytoplasmic masses resem-
bling the cytoplasmic inclusions seen in yolk-sac
tumors (Fig. 6) but with a less striking degree of
PAS-positivity. T h e light microscopical appear-
ances are strongly suggestive of myoblastic dif-
ferentiation. Preliminary electron microscopical
studies suggest that these are indeed myoblastic
lesions.
Clear cell pattern: This variant, depicted in
Figures 7-10, predominated in 11 specimens. It
is characterized by sharply defined polygonal
cells with water-clear cytoplasm and ovoid to
rounded vesicular nuclei in which nucleoli are
inconspicuous. These cells are usually arranged
in nested or trabecular fashion, with fine
spindle-cell septa, often containing prominent

FIG.6. “Khabdomyo-
sarcomatoid” pattern.
Rounded hyaline cyto-
plasmic. masses are pres-
ent in many cells. Note
prominent central nucle-
oli in several cells (H &
E X625).
1944 May 1978
CANCER Vol. 41

FIG. 7. “Clear cell”

sarcomatous pattern.
Delicate spindle cell
septa divide the larger
polygonal clear cells into
parallel c o r d s . O n e
tubular structure is pres-
ent (see text) ( H & E
XUO).

but small blood vessels, separating the tumor
into columns several cells thick. In several in-
stances there was prominent palisading, similar
to that of neurilemmomas (Fig. 10). These tu-
mors seem usually to involve renal medulla, and
distinct epithelial tubules lined by basophilic
columnar cells are singly dispersed throughout
the lesion (Figs. 7 and 9) but we have not con-
vincingly demonstrated them in extrarenal ex-
tension of tumor. We presume that most of these
tubules are preexistent renal elements, but can-
not exclude the possibility that they are a com-
ponent of the neoplasm.
Hyalinizing pattern: This change, depicted in
Figures 11 and 12, is characterized by variably
abundant hyaline acidophilic intercellular ma-
trix separating individual tumor cells and giving
an appearance often resembling malignant
osteoid in osteosarcomas. This change was pres-
ent to a minor degree in several specimens, and
in 2 was the predominant pattern. This hyaline
matrix is not strongly birefringent and at pres-
ent we are unable to characterize it further. I n
two sarcomas no one of the above patterns pre-
dominated, and one bizarre, anaplastic spindle
cell tumor did not correspond to the above three
groups.
Several specimens were entered on the NWTS

FIG. 8. “Clear cell”

sarcoma. Rounded to
polygonal cells with wa-
ter clear cytoplasm char-
acterize this tumor type.
Spindle cell septa con-
taining small vessels are
prominent. Note vesicu-
lar nuclei without con-
spicuous nucleoli, in
contrast to the “rhab-
domyosarcomatoid”
pattern (H & E X 2 0 0 ) .
No. 5 TUMOR Beckwith and Palmer
WILMS’ 1945

FIG. 9. “Clear cell”

sarcoma with numerous
tubules. I n this field the
spindle-cell septa are ab-
sent, and slight stromal
hyalinization indicates
an early transition to-
wards the “hyalinizing”
pattern (H & E X80).

as Wilms’ tumors which we view as uncom- congenital mesoblastic nephroma discussed

monly cellular variants of congenital mesoblas- elsewhere by one of us.
tic nephroma or fetal renal h a m a r t ~ m a . ~ ” ~ In contrast to anaplastic Wilms’ tumors, the
These variants, which we term “cellular mesob- sarcomatous variants were often seen in younger
lastic nephromas,” are of great importance, as patients. Eight of the 24 patients with this type
the four cases so treated on NWTS I all survived of lesion were under two years of age. Seven of
without recurrence, in sharp contrast to the sar- these 8 sarcomatous lesions in younger patients
comatous Wilms’ tumors. We are of course un- proved lethal (Table 2). A total of 10 deaths due
able to determine how these patients might have to tumor in this age group occurred on NWTS I,
fared had treatment been limited to nephrec- of which 7 were related to sarcomatous variants.
tomy. This group of lesions is most easily recog- Another noteworthy feature was a tendency for
nized by their resemblance to leiomyosarcoma, sarcomas to metastasize to bone as previously
and corresponds to the “grey zone” variants of noted by Kidd.“ We found this to be espe-

FIG. 10. “Clear cell”

sarcoma with prominent
nuclear palisading re-
sembling neurilem-
moma. This change was
found in two specimens
(H & E X80).
1946 CANCERMay 1978
cially true of the “clear cell” tumors. O n NWTS
I, 14 patients experienced bony metastases. Of
these, 8 had sarcomatous lesions, 7 being pre-
dominantly of the “clear cell” variety. Another
had focal anaplasia, 4 were nonanaplastic, and
for 1 the original tumor was not available for
review.
As was true for the anaplastic lesions, thera-
peutic regimens used in NWTS I were generally
unsuccessful in preventing relapse of patients
with sarcomatous tumors. First relapse in these
24 children occurred within 1 2 months of diag-
nosis in all but 3 instances, and death due to
tumor occurred after 18 months only twice. As
shown in Table 3, of 12 Group 11-111 patients
with sarcomas assigned to single agent treat-
ment arms, none were relapse free, and 9 died of
tumor. Of 9 assigned combination chemother-
apy (Groups 11-111, Arm C), 3 were free of re-
lapse, and 5 died of tumor. More detailed study
of the structure and natural history of the sarco-
matous variants described above is in progress,
and will be reported subsequently.
T h e extent of tumor at diagnosis was signifi-
cant in determining the outcome of anaplastic
and sarcomatous lesions in this study. Only one
of 9 patients with unfavorable histological pat-
terns in clinical Group I died of tumor. Six of
these patients are free of relapse (Table 3 ) .
DISCUSSION
The results of this study suggest that two
relatively uncommon variants of Wilms’ tumor
have an extremely unfavorable prognosis, and
Vol. 41
FIG. 11. “Hyaliniz-
ing” sarcomatous pat-
tern. When this change
is prominent some foci
superficially resemble
ossifying tumors (H & E
x 200).
contribute heavily to the overall mortality fig-
ures of this tumor when the therapeutic ap-
proaches of NWTS I are used. These anaplastic
and sarcomatous variants comprised only 11.5%
of tumors studied, yet they accounted for 28
(51.9%) of 54 deaths due to tumor. These unfa-
vorable patterns proved to be the most impor-
tant single determinant of patient outcome on
NWTS I . 5Twenty-five patients had tumors with
marked cytological atypia, of whom 14 (56%)
died of tumor. Twenty-four patients had sarco-
matous lesions and 14 (58.3%) died of tumor.
Three hundred seventy-eight patients had t u -
mors in which neither of these features was
found, of whom only 26 (6.9%) died of tumor.
Seven of 10 tumor deaths among 122 patients
diagnosed before two years of age were associ-
ated with sarcomatous variants.
Several prior attempts to relate prognosis to
microscopic structure in Wilms’ tumor have
among which Jereb
been published,3,6,~,11,12,15,~6
and Sandstedt” are the only authors that appar-
ently included both anaplastic and sarcomatous
lesions in their classification. Their histological
Type 111, comprising 27.7% of 122 specimens,
included cases “primarily composed of mes-
enchymal elements,” and all specimens showing
“marked atypia of the blastemic cells.” It is not
clear whether relatively differentiated stromal
tumors would also have been placed in this cate-
gory, such as the “cellular mesoblastic neph-
romas” we have discussed above. It seems from
their description that predominantly blastemal
specimens were also included in Type 111. Only
No. 5 WiLMs’ TUMOR Beckwith and Palmer
6 of 31 tumors in this group were cured by
therapy, and this was the least favorable of the
three histological types they recognized.
I t is fortunate that the findings of the present
study involve histological features that will in
general be easily recognizable to most patholo-
gists. Anaplasia, as we have defined it, is gener-
ally identifiable with ease, though the poten-
tially confounding factors described above must
be kept in mind. It is important to recognize that
even small foci of anaplasia were associated with
unfavorable outcome. T h e various sarcomatous
patterns are also usually recognized without dif-
ficulty, though cellular .mesoblastic nephromas
will occasionally present difficulties. These can
be avoided if any lesion resembling a leiomyo-
sarcoma is excluded from the unfavorable cate-
gory, though the small numbers of such speci-
mens available to us at this time precludes a
final statement on this matter.
A limiting factor in this study was the variable
thoroughness with which tumors were sampled
In 25% of cases, fewer than 4 tumor sections
were available to us, and in some we had only a
single section. I n the case of sarcomatous le-
sions, this is probably not a major problem,
since these tumors are essentially monophasic.
However, anaplasia requires more thorough
sampling, as in over half our cases we found
this change in fewer than 10%of high dry micro-
scopic fields examined. It is probable that some
specimens with anaplastic cells were not sam-
pled well enough to have been so identified in
this study. We are not yet able to give firm
FIG. 12. “Hyaliniz-
ing” sarcomatous pat-
tern with more advanced
strornal change than in
Figure I I . (H & E X80).
1947
guidelines as to the adequacy with which a tu-
mor should be sampled before anaplastic
changes can b e considered absent. Extensive
quantitative study of a large number of speci-
mens will be required before this important
question can be answered. Until the results of
such a study are available, the pathologist must
use empirical guidelines in determining the
number of sections taken. Prior to the emer-
gence of specific guidelines, perhaps minimal
criteria for sampling might be those used in
certain soft tissue sarcoma studies l 3 where one
generous section is recommended for every cen-
timeter of maximum tumor diameter, or ten sec-
tions, whichever number is greater. I n addition,
we would recommend sampling each discrete
nodule whenever the tumor is subdivided in dis-
tinct lobules.
Anaplasia within the primary tumor was usu-
ally correlated with similar cytological changes
in metastatic sites biopsied prior to the onset of
therapy. In two of our specimens, however, ana-
plasia was identified in hilar lymph node depos-
its but not in the available sections of the pri-
mary. These were not included among the
anaplastic cases in this report, though. We pre-
sume that more complete sections of the original
tumor would have revealed this change.
T h e sarcomatous specimens reported herein
are presented as variants of Wilms’ tumor but
they might eventually be considered as entirely
distinct entities. As we have shown, these lesions
have many differences, both clinically and path-
ologically, from the more conventional Wilms’
1948 CANCER
May 1978 Vol. 41

tumor. We have provisionally classified them as
Wilms’ tumor subtypes for several reasons.
Some sarcomatous lesions contain epithelial ele-
ments differing from preexistent nephrons. O n e
specimen in our consultation files exhibits a sar-
comatous lesion in one kidney with a typical
Wilms’ tumor of the opposite kidney. While
some or all of the patterns we have described
may eventually be separated from the Wilms’
tumor spectrum, we prefer for the present to
retain them within the group, as we do the more
or less monophasic tubular and blastemal speci-
mens.’
T h e results of this study suggest that histolog-
ical classification into “favorable” and “unfa-
vorable” patterns, determined by careful exami-
nation of multiple sections of primary tumor, of
all regional lymph nodes, and of metastatic sites
accessible to biopsy, should be an integral factor
in the design of future treatment protocols. Fu-
ture changes in the direction of increased ag-
gressiveness and increased risk of toxicity should
be directed primarily at the tumor in which
cytological atypia or sarcomatous pattern is evi-
dent. For the remainder of cases, relapse and
mortality rates are sufficiently low to permit
consideration of reduction in therapeutic aggres-
siveness for certain patient categories.

ADDENDUM

After submitting this manuscript, we have observed three tumors within which well differentiated striated muscle cells
had undergone degenerative changes due to local factors such as ischemia or hemorrhage. The cytodegenerative changes
rrsembled reaction to injury in normal skeletal muscle, in that nuclear enlargement, pleomorphism, and hyperchromatism
were prominent, but atypical mitotic figures were not a feature. This change should therefore be added to the list of pseudo-
anaplastic phenomena on page 1941. I t should be re-emphasized that anaplasia, as the term is used in this paper, can only
be diagnosed when threefold nuclear enlargement, hyperchromasia, and atypical mitotic figures are all present within the
tumor cells.

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