MALIGNANT
PHEOCHROMOCYTOMA
Report
of a Case
in a
I 2-Year-Old
Girl
Thomas E. Cone, Jr., M.D., Captain (MC) USN,
and Howard A. Pearson, M.D, LCDR (MC) USN
United States Naval Hospital, National Naval Medical Center, Bethesda, Maryland
(Submitted December 7, 1962; accepted for publication February 8, 1963.)
The opinions or assertions contained herein are the private ones of the writer, and are not to be
con-strued as official, nor as reflecting the views of the Bureau of Medicine and Surgery of the Navy Depart-ment, or the Naval Service at large.
ADDRESS: (T.E.C.) U.S. Naval Hospital, Bethesda 14, Maryland.
PEDIATRICS, October 1963
LTHOUGH an ever-increasing number of
children with pheochromocytoma is
being reported, the occurrence of a
malig-nant pheochromocytoma in the pediatric
age group is rare. In fact, a search of the
literature available to us has revealed only
three children in whom this diagnosis
could be considered.13
It is generally accepted that a diagnosis
of malignant pheochromocytoma cannot be
made in the absence of metastases,
irrespec-tive of the histologic picture, and
notwith-standing the presence or absence of
in-vasion of the tumor capsule or the
sur-rounding blood vessels.
The case we are reporting is the first in
the pediatric literature to meet the
strin-gent criteria for a diagnosis of malignant
pheochromocytoma, as formulated by
Davis and co-workers, namely, that
me-tastases should be present at a site where
aberrant endocrine tissue is not otherwise
found, and the secretory function should
be proved by the presence of the
appro-priate hormone in the metastases and their
secretions. In fact, a search of the recent
literature would indicate that very few of
the cases reported would meet these
strin-gent criteria68; none of these cases have
been in children.
This case was reported by us in l957
(Case 3). At that time, a large, functionally
active pheochromocytoma was surgically
removed from the region of the aortic
bi-furcation (organs of Zuckerkandi), as well
as a smaller one from the superior pole of
the right adrenal gland; the girl was one
of several members of a family with a
history of pheochromocytoma. Following
the initial operation 6 years ago, an
ex-cised lymph node that had been in
juxta-position to the larger of the two
pheo-chromocytomas was found on histologic
examination to contain chromaffin cells.
Although the presence of such cells in the
excised lymph node was thought to
rep-resent compression and invagination of
the node rather than a true metastasis,
malignancy of the tumor was considered
possible. The subsequent clinical course,
and the operative findings at the second
laparotomy, 6 years after the first,
demon-strated malignancy. Of course, irrespective
of histologic findings, all
pheochromocy-tomas are physiologically malignant.
CASE REPORT
C. N.,
a 12-year-old, white girl, wasad-mitted for the sixth time on September 1,
1961, because of persistent hypertension
detected 2 months prior to the first
admis-sion, 7 years previously.
First Admission
When the patient was 6 years old, her
blood pressure fluctuated from 180 to 300
systolic and 120 to 210 diastolic. In the
suprapubic area, extending to within 5 cm
of the umbilicus, a 5-by-5-cm nonpulsating
mass was palpated.
The concentration of catecholamines in
532
(normal, 2 to 5 &g/1) with no
demonstra-ble epinephnmne. At laparotomy, a dusky,
white, multinodular 5-by-3-cm
pheochrom-ocytoma was found encircling the aorta
in the region of the aortic bifurcation
(or-gans of Zuckerkandi) and extending
up-ward into the base of the mesentery. Also,
a 1.5-by-i-cm right suprarenal
pheochrom-ocytoma with the same macroscopic
ap-pearance as the tumor was found in the
region of the aortic bifurcation. On frozen
section, an enlarged lymph node which
had lain on the anterior surface of the
.larger tumor was reported to contain a
nidus of tumor cells.
Since no distinct plane of cleavage
ex-isted between the larger tumor and the
aorta, complete surgical removal of this
tumor was not attempted because to have
done so would probably have necessitated
an aortic graft for which no preoperative
preparations had been made.
The preoperative diagnosis of
pheo-chromocytoma of both excised tumors was
confirmed histologically. Of particular
in-terest was the microscopic examination of
the lymph node which had been removed
with the tumor from the site of the aortic
bifurcation; serial sections of this
,
nodedisclosed a mass of ectopic chromaffin cells
surrounded by areas of normal lymphoid
tissue.
Cause of Illness
The course of illness during the 6-year
interval between the initial and the
pres-ent admission was satisfactory except for
persistent hypertension and elevated
cate-cholamine levels. The patient returned to
school, grew, and developed normally.
Ex-cept for an occasional upper respiratory
illness, she had no specific medical
com-plaints. However, she did continue to be
emotionally labile, and often had
unpro-voked crying spells and temper tantrums.
A summary of the plasma and urine
cate-cholamine values,
VMA
(vanilylmandelicacid) levels, and blood pressures during
this 6-year period is given in Table I.
Dur-ing this period the blood pressures
fluctu-ated between 150-230/110-140 mm Hg.
The lower values were noted during a
period of approximately 3 years, during
which time she was treated with
phenoxyl-benzamine hydrochloride, an adrenergic
blocking agent. On a daily dose of 40 to
60 mg of this drug, the blood pressure
re-mained relatively steady at 140/120 mm
Hg, without the erratic fluctuations
pre-viously observed.
Present Admission
The continued hypertension, associated
with persistently elevated values of
pres-sor amines, was thought to result from the
presence of a functionally active
pheo-chromocytoma, which could be either
be-nign or malignant. The girl was, therefore,
admitted for a second laparotomy to
re-move any residual pheochromocytoma, if
present.
Physical and Laboratory Findings: On
admission at age 12 years the girl weighed
65 kg and was 142.5 cm high. The blood
pressure in the right arm was 174/120 mm
Hg, left arm 160/120, right leg 250/190,
and left leg 240/190. The ocular fundi
showed an increased A-V ration, with
marked constriction of the arteriolar tree
of both eyes. The heart was not enlarged;
but a grade I to II, short-blowing,
holo-systolic murmur was heard best at the
third left intercostal space. A well-healed
transabdominal scar was present.
The blood and the urine examinations
were within normal limits except for the
detection of elevated levels of pressor
amines in the urine. An excretory urogram
displayed normal renal shadows.
Twenty-four-hour urine studies for
3-methoxy-4-hydroxymandelic acid
(vanillyl-mandelic acid, or VMA) showed elevated
values of 10.3, 10.6, and 8.6 mg/24 hours
on three consecutive days; 6.8 mg/24 hour
is the upper limit of normal for VMA
de-terminations in our laboratory.
Surgical Findings: The abdomen was
3.5-ARTICLES
533
TABLE I
PERTINENT CLINICAL DATA OBTAINED JUST PREVIOUS TO PATIENT’S INITIAL SURGICAL INTERVENTION FOR
REMOVAL OF PHEOCHROMOCYTOMAS UNTIL THE PERIOD JUST FOLLOWING LAST HOSPITAL ADMISSION,
SEPTEMBER 1955-DECEMBER 1961
Month, Year
Plasma Urine
Blood
Pressure (mm Hg) Catecholamine Values Pressor Amine Values
Norepinephrine
(Mg/I)
Epinephrzne
(pg/i)
Catecholamines
(jig/54 hr)
VMA
(mg/54 hr)
180-300
September, 1955 17 0 . ..
1o-10
October 14, 1955 Laparotomy performed-two pheochromocytomas removed
170
November, 1955 10 0 . . . .
-140
180-0
March, 1956 . . . . 300
130-190
160
August, 1957 18 0.8 . .
-10
180
December, 1958 . . . . 07
-110
150-180
April, 1959 16 0. ..
110-130
150
July, 1959 . 30
-110
140
November, 1959 .. 180
-10
140-190
July, 1960 0 .4 80 ..
110-130 10.3, 10.6, 160-174
September, 1961 . . . . . &8.6
120-10
September 14, 1961 Second laparotomy performed-multiple pheochromocytomas removed
100-180
October, 1961 . . . . . 0 & 7
100-110
160-190
November, 1961 .. . . 340 ..
110-HO
180
-FIG. 1. Five of the seven excised specimens con-taming chromaffin tissue : (1) pheochromocytoma
of retroperitoneal area; (2) nodule from area to the left of the distal aorta; (3) periaortic lymph
nodes; (4) lymph node from mesentery of the
left colon; and (5) lymph node from the ligament of Treitz.
cm tumor lay in the retroperitoneal area
just lateral to the origins of the left
corn-mon iliac artery and the distal aorta (Fig.
1). This tumor, absent at the time of
mi-tial surgery, was brown in color, and in
gross appearance was suggestive of a
pheochromocytoma. Further exploration
revealed seven additional smaller tumors
in the area extending from the aortic
bifur-cation cephalad to the ligament of Treitz.
FIG. iA. Photomicrographs of specimen from one of the two pheochromocytomas
535
TABLE II
CONCENTRATION OF CATECHOLAMINES IN Pnru AU V Tuaou AND METASTATIC SITES
Site
Concentration of
Catecholam rues
Norepinephrine Epinephriue
(uzg/gm
tunror tissue) tumor tissue)
Tumor, region of
aortic bifurcation
Lymph node, left
iliac region
Lymph node, ligament
of
2.74
1.25
0.027
ARTICLES
All were excised; five are shown in Figure
1. In the area of the initial dissection, to
the left and posterior to the aortic
bifur-cation, a tumor, apparently residual from
the first operation, was found and easily
removed.
Histologic Findings: Histologically the
two tumors were pheochromocytomas; six
of the seven excised nodules were lymph
nodes containing metastatic nests of
chrom-affin cells. The microscopic pattern of the
excised specimens containing chromaffin
tissue was essentially the same; all
con-tamed numerous islands and collections of
elongated, large, polyhedral cells with
ovoid, slightly granular nuclei and
abun-dant granular cytoplasm (Fig. 2 A-D). The
cytoplasm stained red-brown to red-yellow
in the portions fixed in Zenker’s and Kose’s
solutions.
, ‘
.
V .“ . s.
,: #{248},.,
.
t,
I’2.00 0.006
All three of the excised masses secreted
norepinephrine and epmnephrine
(
TableII). Catecholamine determinations were
,
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Fic. 2B. Specimens of second of the two pheochromocytomas removed from the
region of aortic bifurcation.
%
.
FIG. 2C. Specimen of lymph node containing aberrant nests of hormonally activu
chro-maffin cells (pheochromocytes), from region of the ligament of Treitz.
not made on the other excised masses
which contained chromaffin cells.
Subsequent Course
The postoperative period was
unevent-ful. The blood pressure remained elevated
in the range of 160 to 180 mm Hg systolic,
and 100 to 110 diastolic. Two elevated
un-nary VMA values, 20 and 27 mg/24 hr
(normal 0.7-6.8 mg/24 hr), were obtained
in the first postoperative month. Two
months after the patient’s discharge from
the hospital, the presence of additional,
functionally active but undetected
chrom-affin tissue was further supported by the
finding of a norepinephnine level of 13 p.g/1 of plasma.
COMMENT
During the past 15 years our knowledge of pheochromocytomas has evolved from the statement that there were no reported cases of this syndrome in young children
or infantslO to the present point where
more than 80 pediatric cases have been
1 1 Further in the course of these
15 years, pediatricians have learned that
a pheochromocytoma may be familial,12
extra-adrenal in and
malignant, as this case demonstrates.
Approximately 60 cases of malignant
pheochromocytoma have been reported.
However, in many of these cases the diag-nosis was made largely on histologic
ap-pearance. The cytologic appearance of th
tumor is important, but is not definitely
diagnostic of a malignant neoplasm, as
shown in the excellent study of the
path-ological aspects of pheochromocytoma by
Symington and Goodall. In fact,
Mc-Gavack and colleagues’ have shown that
the histologic features descriptive of
malig-nancy are equally characteristic of benign
pheochromocytomas. These and other au-thors have stated that in the present stage of our knowledge all pheochromocytomas without proven metastases should be clas-sified as benign.’ Even the so-called
be-nign tumors may exhibit characteristics
FiG. 2D. Specimen of lymph node from mesentery at left colon.
ARTICLES 537
blood vessels, which in other tissues would
be accepted as prima facie evidence of In
It should be emphasized that
pheo-chromocytomas may occur simultaneously
in several sites normally occupied by
chromaffin cells, and in this way, multiple
simple tumors may occur.179 Whether
multiple tumor growths may be considered
as metastases from a primary
pheochromo-cytoma will depend more on the site than
on the nature of the cells within the sec-ondary sites. If the cells characteristic of
a pheochromocytoma are present in any
location where chromaffin tissue is
ct:s-tomarily found, and especially if the
tu-mor cells are mature pheochromocytes,
then a multicentric origin must be
con-sidered as the true mechanism for
second-ary deposits.2o
The strictest criteria for the diagnosis of
malignancy are those formulated by Davis
et al. These authors state that histological
similarity of a secondary deposit to a
pri-mary tumor does not prove similarity of
function; metastases should be present at
a site where aberrant endocrine tissue is
not otherwise found, and the secretory
function should be proved by the presence
of the appropriate hormone in the me-tastases and their secretions. These
cri-teria are so stringent that to our knowledge
only three previously reported cases68
would meet them; none of these were in
children. The case we are reporting is therefore the first to comply with the stringent criteria for the diagnosis of a
malignant pheochromocytoma as
men-tioned above.
Universal acceptance of these rigid
standards should help to overcome much
of the confusion regarding the diagnosis
of a malignant pheochromocytoma,
be-cause one cannot depend on the histologic
appearance of tumor cells in the
metas-tases as a criterion for malignancy or be-nignity.14 Such cells may be mature
pheo-chromocytes similar to those in the primary
lesion,2’ or immature cells
(pheochromo-blasts),22 or a mixture of both.23 Even
in-vasion of the capsule or the blood vessels
it-self, sufficient evidence to make an
un-equivocal diagnosis of malignancy.2 It
should be mentioned that although the
criteria of Davis et a!. will help in
estab-lishing a diagnosis of malignancy in most
cases, these criteria may not be applicable
in all, because our knowledge of the
bio-chemical nature of tumors of neural crest
origin may not yet be sufficient to suggest
that all metastases of malignant
pheochro-rnocytomas will produce detectable
amounts of catecholamines or their
pre-cursors. But since a diagnosis of malignant
pheochromocytoma depends on the
pres-ence of metastases, serial measurements of
urinary catecholamines, their precursors
and metabolites, not only preoperatively
but postoperatively, would be paramount
in establishing this diagnosis.
The survival span after diagnosis of
ma-lignant pheochromocytoma has been
es-tablished is usually less than 3 years,
ac-cording to Palmieri and coworkers.8 Our
patient is more fortunate than most
be-cause she is still alive and reasonably well,
6 years after her first operation.
SUMMARY
A case of malignant pheochromocytoma
during a 6-year period in a 12-year-old,
obese, white girl represents the first
re-corded case to meet the most stringent
cri-teria for a diagnosis of malignant
pheo-chromocytoma, namely, that metastases
occur at a site where aberrant endocrine
tissue is not otherwise found, and that
secretory function be proved by the
pres-ence of appropriate hormone in the
me-tastases and their secretions. Studies of
the clinical course of pheochromocytoma
in children during the past decade and a
half have shown that this tumor may be
familial, may frequently be extraadrenal,
may be recurrent, and may be malignant,
as demonstrated by this case.
REFERENCES
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(paraganglioma malignum) with
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Laeg., 117:1405, 1955.
2. Evans, W. F., and Stewart, H. J.: The
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feochromocytom s paroxysm#{225}lni
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Cas L#{233}kCesk., 94:8, 1955.
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10. Thorn, G. M. : In Cecil, R. L. : A Textbook
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ARTICLES
53917. Cahill, C. F., Pheochromocytoma. J.A.M.A.,
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18. Snyder, C. H., and Vick, E. H.:
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Acknowledgment
We should like to thank Lt. Col. Edward C.
Knoblock, MSC, Director, Division of
Biochem-istry, Walter Reed Army Institute of Research,
for determining the catecholainine values of the
