bulletin of the new york academy of medicine january i966 tumors of dysgenetic gonads in intersexes

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BULLETIN OF
THE NEW YORK ACADEMY
OF MEDICINE
VOL. No. I JANUARY I966
42,
TUMORS OF DYSGENETIC GONADS IN
INTERSEXES: CASE REPORTS AND
DISCUSSION REGARDING THEIR
PLACE IN GONADAL ONCOLOGY*
MEYER M. MELICOW
Squier Urological Clinic, Columbia-Presbyterian Medical Center
New York, N. Y.
THE "battle of the sexes" begins early in intrauterine life. Gestation
takes place in a maternal estrogenic environment. Thus it becomes
necessary, in dealing with male embryos, to have some factor(s) to
counteract this influence, else all individuals, irrespective of genotype,
would be born as female phenotypes. It is the Y chromosome which
determines medullary dominance in the bisexual gonad, converting it
into a testis. It is the latter, with its morphogenic hormone, that inhibits
the cortex and maternal estrogens.1', Thence, in the struggle between
the two bisexual duct systems, it is again the normal testis with its
hormone that gives dominance to the wolffian over the mullerian duct
systems.3 The prenatal function of the male gonad is culminated by
the eighth month of intrauterine life when it completes the conversion
of the external female genital anlage into external male genitalia: the
*Presented at the meeting of the Section on Urology at The New York Academy of Medicine,
October 21, 1964. This investigation was aided by funds from the Irene Heinz-Given and John
La Porte Given Foundation, New York, N. Y., and a John Given, Jr., gift.
4 4M1A.{. AMl.. MMEELLIICCOOWWV
labia majora are fused, forming a scrotum that harbors the descending
testes, the vagina and uterus remain attenuated, and the labia minora are
moulded into a trough and later into a tube that extends forward as
the urethra through the enlarging and lengthening clitoris; thus chang-
ing that anlage into a penis. In the absence of the Y chromosome or in
agenesis of the medulla, the mullerian system takes over and the in-
dividual is born a female phenotype. Should the medulla be defective,
then wvolffian elements fail to dominate while mullerian elements are
only partly inhibited and, as a result, there is relative failure in the con-
version of the female external genital anlage into an adequately func-
tioning typical male apparatus. Thus the commonest cause of male
pseudohermaphroditism is a deficient testis (i.e. dysgenetic during em-
bryological life).' Such an individual is an arrested incomplete male
phenotype harboring mullerian remnants, and the earlier in fetal life the
testicular inadequacy occurs, the more widespread and pronounced is
the defect. Consequently male pseudohermaphroditism ranges from the
mild case whose chief problem is hypospadias, through cases with a
cleft scrotum and persistent urogenital sinus and undescended, usually
dysgenetic testes, to the profound alteration in phenotype associated
with testicular agenesis (Turner's syndrome), or the type of dysgenesis
that is characterized by absence of spermatogones and dominance of
Sertoli cells, namely the "feminizing" testis.
The commonest cause of female pseudohermaphroditism, on the
other hand, is not a deficient (dysgenetic) or aplastic ovary. A sex
chromatin positive fetus with ovarian agenesis or dysgenesis can still
develop into a phenotypical female although with deficient feminine
attributes, i.e. short vagina, small uterus, undeveloped breasts, primary
amenorrhea, etc. Wolffian elements are not retained unless there is an
accompanying androgen excess. The commonest cause of female pseu-
dohermaphroditism is the androgen excess that occurs in congenital
adrenal cortical hyperfunction or in postnatal cortical hyperplasia or
neoplasia.4 5 Virilization can also result from a hilar cell tumor, or
thecoma, etc., or it can be induced iatrogenically by administering
androgens or progesterone during pregnancy."
LIFE CYCLE OF THE DYSGENETIC GONAD
The dysgenetic defective gonads of XX or XY embryos showed
varying degrees of failure in differentiation. In extreme cases, no recog-
Bull.N.Y.Acad.Med.
TUMORS OF DYSGENETIC GONADS IN INTERSEXES 5
nizable gonadal elements could be found (gonadal agenesis). In some,
only a vestigial remnant composed of whorls of stromal tissue, at times
reminiscent of an ovarian cortex devoid of germ cells, was encountered
(gonadal "streak"). This represented a pronounced degree of gonadal
failure and was observed in many patients with Turner's syndrome. In
a fairly large number of other types of intersexes, however, some
recognizable gonadal tissue was found (true gonadal dysgenesis).7 The
dysgenetic gonad was usually smaller than normal, somewhat elongated,
and was composed of nests of round, fairly large "germ" cells with
clear cytoplasm and prominent round nuclei of varying size. These
cells have been labeled "neuter cells"8 because they apparently lacked
the capacity to differentiate into functioning germ cells (spermatogones
or ovocytes). Instead many of them degenerated and formed laminated
concretions and calcospheroids. The two findings-large round cells with
prominent nuclei and clear cytoplasm, and calcification-were the
stigmata of a gonad which was defective or had been arrested early in
embryonal development. Coupled with the degenerative tendency of
these imperfect gonads was a slow hyperplasia and, in some instances,
neoplasia. Sohval9 in 1956 called attention to this association between
testicular (gonadal) maldevelopment and neoplasm. When the neo-
plastic change occurred, one could not be certain whether the tumor
of these "clear" cells was a variation of seminoma'0-13 or dysgermi-
noma,14-19 and for that reason the terms gonadoblastoma, neuter cell
tumor, gonocytoma, dysgenetic gonadoma, have been proposed.8' 20-28
Furthermore, in gonads that contained not only "neuter" cells but also
some identifiable spermatogones or ovocytes, the neoplastic process
often involved also the latter types of cells,29 and then the question of
ruling out a neoplasm arising in the bisexual gonad of a true herm-
aphrodite could not always be resolved.10' 30 Cells resembling either
the granulosa or Sertoli types were often also present, while other foci
contained theca, hilar, or interstitial cells. Occasionally, they too under-
went hyperplasia or neoplasia, thus complicating both the clinical and
histological picture.31-6 Dysgenetic gonads that have become neoplastic
have been reported in siblings.37
It is important to note that a biopsy of a dysgenetic gonad may not
be representative of the rest of the gland. Furthermore, it is not enough
to state "gonadal dysgenesis"; one should add a description as to the
status of the germinal and nongerminal elements. It may be impossible
Vol.42,No. 1,January1966
6 M. M. MELICOW
6 M. M. MELICOW
to refute the argument, in some cases, that the bizarre pattern may be
masking a bisexual gonad.
We noted that during the life cycle of a dysgenetic gonad, one or
more of the following events took place: i) the neuter sex cells re-
mained static; or 2) they showed progressive degeneration and formed
a calcific mass; or 3) some clusters of neuter cells underwent hyper-
plasia and/or neoplasia (gonadoblastoma, gonocytoma, dysgenetic
gonadoma, or neuter cell tumor), accompanied by varying degrees
of degeneration and accumulation of concretions; or 4) the nongerminal
elements became hyperplastic or neoplastic (interstitiomas, androblas-
tomas, thecomas, sertoliomas, granulosa cell tumors, tubular adenomas,
hilus cell tumors, or combinations such as gynandroblastomas, etc.)
and these neoplasms were slow-growing and rarely malignant, as al-
ready indicated; 5) in those dysgenetic gonads that contained not only
neuter cells but, in addition, some functioning germ cells, seminomas
or dysgerminomas (often multifocal) and even embryonal carcinomas,
teratocarcinomas, adult teratomas, or choriocarcinomas29 also developed.
The presence of a neoplastic dysgenetic gonad could be detected readily
when in the labia (or cleft scrotum). The abdominal masses, however,
were usually missed and, on occasion, were discovered incidentally
during a general examination. In some instances the sudden twist or
torsion of the pedicle from which the neoplastic gonad hung induced
an acute abdominal condition leading to exploratory laparotomy and the
finding of the infarcted mass.
THE PHENOTYPE IN GONADAL DYSGENESIS
The phenotype of individuals with neuter gonads, irrespective of
sex chromatin pattern, tended towards femininity. The genitalia were
ambiguous. The phallus resembled either a small penis or clitoris. The
labial swellings or cleft scrotum were either devoid of gonads or con-
tained very small ones, the urethra and small vagina opened into the
urogenital sinus, and the mullerian and wolifian remnants intermingled
in varying degree. The phenotype of a patient with gonads that were
defective but recognizable as "ovaries" and with positive sex chromatin
usually remained isosexual (feminine). The external (and internal)
feminine genitalia were poorly developed or deficient. However, in
rare instances some focus of androgen production within the gonad
developed later in life and virilization followed. The phenotype of
Bull.N.Y.Acad.Med.
TUMORS OF DYSGENETIC GONADS IN INTERSEXES 7
XY individuals with congenitally deficient but histologically recogniz-
able testes ranged from complete feminization in those with feminizing
testes, to varying degrees of masculinity in patients with micro- or de-
fective testes, particularly when raised as males. The declared sex in
the nursery depended on the impression gained on inspection of the
genitalia. In some instances subsequent genital and somatic development
were at variance with the original impression bringing with it doubt,
anxiety, and frustration to the subject and/or the parents.
Children with feminizing testes, being phenotypical females, were
raised as girls. They and their parents were usually unaware of any
abnormality, except when inguinal masses were discovered and diag-
nosed clinically as hernias. However, during surgery the nodules were
found to be testes and the nuclear sex chromatin pattern was negative.
In other cases suspicion as to the possibility of a sexual abnormality
did not arise until puberty, because the expected menarche did not
occur. The breasts, however, usually enlarged. Often medical advice
was not sought until much later and then only because of inability to
conceive. In some, hirsutism developed and other evidences of andro-
genicity; and in these instances, biopsy or removal of the gonad(s)
revealed pronounced interstitial cell hyperplasia or hilar cell tumor. A
uterus and tubes were usually absent.8',38-45
The more frequent deviations in phenotype of sex chromatin nega-
tive individuals with dysgenetic gonads ranged from deficient maleness
(such as sparse facial hair, fine skin, some hippiness, etc.) to complete
masculine build. The bizarre ambiguous external genitalia were the con-
cern of the patient, who carried such a "skeleton in the closet" to the
grave; other such patients lived unhappily as "females" and others as
frustrated "males." The severity of the genital malformation, or the
degree of awareness and anxiety caused by the abnormality, determined
if and when medical help was sought.
GONADOBLASTOMA
It is understandable why a dysgenetic gonad tends to undergo de-
generative changes, but why there is also a tendency in many instances
for the surviving cells to show hyperplasia or neoplasia is a fascinating
and puzzling phenomenon. It is thought by some that this may be the
result of an imbalance in the pituitary-gonadal axis. The nonfunction-
ing or dysfunctioning gonadal cells fail to inhibit the pituitary gland,
Vol.42,No. 1,January1966
8
M. M. MELICOW
8 MELICOW
whose secretions bombard and stimulate the gonadal target cells into
multiplying. This may explain hyperplasia but not neoplasia.
The characteristics of gonadoblastoma (neuter cell tumor, gono-
cytoma, dysgenetic gonadoma, etc.) were as follows:
i) The mass was either smaller than the normal gonad, or moder-
ately enlarged, and sections revealed scattered clusters of germ cells re-
sembling those in the indifferent stage of the bipotential gonad (i.e.
the gonadal blastema). The neoplasms were slow-growing and non-
invasive.
2) In some cases the few spermatogones (or ovocytes) that were
present also partook of the neoplastic process and, as a result, developed
large malignant growths.12,16, 18, 19, 46
3) Groups of nongerminal cellular elements, when present, also
tended to undergo hyperplasia or neoplasia.47
4) Concretions, at time laminated, often nondescript, were com-
monly found.
It is extremely important to emphasize the difference between neo-
plasms of dysgenetic gonads and those that developed in individuals
who were not intersex and whose gonads had apparently been rela-
tively normal prior to neoplastic change. The classification of the
latter types of tumors is fairly well understood. It has been postulated
by many pathologists that in the male the neoplasms arise from adult
germ cells that line the seminiferous tubules; for this reason they are
designated "germinal" tumors. In the embryonal types (embryonal
carcinoma, choriocarcinoma, teratocarcinoma, etc.) it is postulated
that we are dealing with malignancies that develop from germ cells
that are totipotent, capable of producing embryonal elements during
their unbridled growth.4852 In the group designated as seminomas, the
neoplasms also arise from germ cells; but it is thought that these germ
cells, in dividing, do not release their trigerminal potential.49' 50 They
are in a sense atrophic. The gonadoblastoma, on the other hand, ap-
parently forms from "neuter" (germ) cells that either never possessed
this potential or were deprived of it early in development. Thus the
embryonal carcinomas, etc., tend to develop in testes with functioning
spermatogones, the seminomas tend to arise in an atrophic testis, with
"depressed" spermatogones, while the gonadoblastomas tend to form
from the nonfunctioning primitive ,neuter germ cells in embryologically
deficient gonads (Figure i). It is of interest to note that the embryonal
Bull.N.Y.Acad.Med.
TUMORS OF DYSGENETIC GONADS IN INTERSEXES 9
Fig. 1. Schematic representation of the place occupied by gonadoblastoma in the
classification of testicular tumors. It is presumed that this tumor would occupy a
similar position in a schema of ovarian neoplasms.
carcinomas occur mostly in young adult nmales50 and, experimentally,
more readily in fowl if the carcinogenic agent is administered during
spring at the height of sexual maturation and activity;53 the seminomas,
on the other hand, develop in older people, more often in undescended
atrophic testes46' 51-57 and in laboratory animals whose testes have been
exposed to injury or radiation.
Since dysgenetic gonads are congenital, the impulse to undergo
hyperplasia or neoplasia can occur early in childhood. Many tumors re-
moved at this stage that have been reported as adenocarcinomas with
clear cells,61' 62 or as endodermal sinus tumors,63' 64 or as variants of semi-
noma,11-13 probably belong under the category of gonadoblastoma.
Tumors reported as arising from the "specialized gonadal stroma"33
i.e. sertoliomas, granulosa cell tumors, thecomas, hilus cell tumors, inter-
stitiomas, etc., are grouped under the heading of nongerminal tumors.
FEMINIZING TESTES
These perverse gonads, traitors to their sex, apparently induce or
are associated with a complete phenotype reversal. The syndrome mav
Vol.42,No. 1,January1966
I 0 M. M. MELICOW
I0 M. M. MELICOW~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
be familial and has been known to occur in siblings.4' 43 In some of
the patients the microgonads lay in the pelvis, in others near the internal
rings, and in some they presented externally as nodules within the
labia. They were composed of small seminiferous tubules lined mostly
by Sertoli cells. On occasion, clusters of smaller tubules were seen
lying like islands surrounded by the larger structures. These have been
labeled tubular adenomas.32 33,38 39 65 66 The interstitial cells were nu-
merous but apparently nonfunctioning. However, insomeinstances, par-
ticularly in older patients, virilization did occur, and in these the Leydig
cells' hyperplasia was pronounced. In the majority a uterus, broad liga-
ment, fallopian tubes and cervix were absent, but a small blind sac
representing a vagina was present. In a few cases, however, all ele-
ments of the mullerian system were found in varying degree.
CASE REPORTS
At present an accurate statistical analysis of the incidence of gonado-
blastoma and related tumors in dysgenetic gonads is not available. In
most instances the tumors were discovered during adult life, so that
the appearance of the gonad-in infancy and childhood was not known.
Furthermore, the significance of the unique histologic pattern in the
excised neoplasms was not appreciated. In the rare case in which a
gonadal biopsy was obtained in infancy or childhood, the diagnosis
was "immature" testis (or ovary) and the import of the "clear cells"
not realized. Gradually a number of reports appeared that revealed a
progressive awareness in regard to the special cytological pattern of
tumors arising in congenitally defective gonads. Thus Scully, in I953,
used the term gonadoblastoma;20 Spielman and Motyloff, in 1955, dis-
cussed "neuter" cell tumors;8 Sohval, in 1956, discussed testicular dys-
genesis in relation to tumors of testis;9 Teilum, in I958, included the
gonadomas among testicular, ovarian, and Sertoli cell tumors;31 Melicow
and Uson, in I959, used the term "dysgenetic gonadoma;"'21 and Teter,
in i960 and i96i, suggested "gonocytoma, types II and III" for these
neoplasms.22 23 Reports of adenoma in feminizing testes are not un-
common.34,38,39,41
Following are some case reports of gonadoblastomas (three cases)
and tubular adenoma (one case), from the files of the Babies Hospital,
Squier Urological Clinic, and Department of Pathology of the Colum-
bia University Presbyterian Medical Center, New York, N. Y.
Pull.N.Y.Acad.Med.
d
Fig. 2
Fig. 2. Case 1: G.K., an 81/2-year-old, sex chromatin negative intersex, raised as male.
Note small phallus (a) and cleft scrotum (b). Biopsy of the left gonad (c) shows some
seminiferous tubules and stigmata of gonadal dysgenesis. At 17 years of age the
patient returned for left herniorrhaphy. The left gonad was removed and was the site of
multiple gonadoblastomas (d and e), and a seminoma (f). Note calcifications.
I 2 AlI. AlI. AIELICOW
M. i\L. MJLLICOW
Case i
Gonadoblastoma and dysgerminomna. G.K. (P.H. No. 915930), a
17-year-old intersex in whom a biopsy of the same gonad, obtained
nine years earlier, was diagnosed as a dysgenetic gonad. The pa-
tient was born with ambiguous genitalia, but declared to be a male
because of a large phallus that was, however, incurvated and hypo-
spadic, and the cleft scrotum was empty. Laparotomy, elsewhere, when
the child was four years of age, had revealed a "transverse fold" of peri-
toneum extending from one lateral wall of the pelvis to the opposite,
and two intra-abdominal gonads. B1iopsy of the riglht one rev-ealed an
"immature testis." Later, when the patient was 811 years of age,
laparotomy was again performed and biopsies of the gonads repeated.
The right one xvas at first labeled an ovariotestis but later this Was
changed to "probably testis," the left one wvas diagnosed as "juvenile
testis." TIe uterus, right tube, and right gonad were removed, and an
attempt was made to bring down the left gonad through the left
inguinal ring. The tiny right gonad measured only0.5 X 0 75 cm., and
sections showed the pattern of dysgenesis. Nine years later the patient,
then almost i8 years of age, underwent a left inguinal herniorrhaphy
during which a repeat biopsy of the left gonad revealed the character-
istic pattern of gonadoblastoma and foci suggestive of dvsgerminoma
and of Sertoli cell hyperplasia (Figure 1).
Case 2
Gonardoblastoma in an intersex raised as male with bizarre genitalia.
J.M. (P.H., No. 957417), 22 years of age, short of stature, broad hips,
male hair distribution, and small incurvated penis with perineal hypo-
spadias and urogenital sinus. There was a cleft scrotum, and an oval
mass, thought to be a testis, was palpated in the right inguinal canal.
The I7-ketosteroids measured IO mg., and estrogens 41.i8 rat units in a
24-hour urine sample. A urethrogram disclosed a relatively short urethra
and a funnel-like cavity (vagina and uterine lumen) with a linear
extension in the direction of the calcified mass. The intravenous uro-
gram demonstrated a normal upper urinary tract and indicated that the
calcific shadow was extraurinary. Exploratory celiotomy revealed a
small uterus with a left broad ligament, and a large ovoid mass replac-
ing the left gonad. All were excised except the small right gonad, which
Bull. N.Y.Acad.Med.