UTERINE ADENOMATA IN THE RABBIT
I. CLINICAL HISTORY, PATHOLOGY AND PKELr~rr~ARY
BY HARRY S. N. GREENE, M.D., AND JOHN A. SAXTON, JR., M.D.
(From the Department of Animal and Plant Pathology of The Rockefeller Institute foe
Medical Research, Princeton, New Jersey)
PraTeS 28 to 31
(Received for publication, February 1, 1938)
In view of the widespread use of the rabbit in experimental labora-
tories and the scarcity of recorded instances of uterine adenoma and
adenocarclnoma, it would appear that these tumors are of extremely
low incidence. Polson (1) in a study of the incidence up to 1927
cited 29 instances, and a review of the subsequent literature yields only
a few additional cases. It is of interest, therefore, that during the
past 4 years in a colony of approximately 500 female rabbits more
than 80 such tumors have been found.
Past reports have been limited to the pathological examination of
tumors which were first observed at autopsy, and the clinical course
has not been described. Attempts to transplant the tumor were
made in the majority of the recorded instances but were uniformly
unsuccessful. On the other hand, in many of the cases included in
the present report, the presence of the tumor was noted during life
and the clinical course followed to death or disposal.
transplantation has been successful and growth has been obtained
in the 6th series of transfers.
The object of this paper is to record the present high incidence of
the tumor and to describe its clinical history, pathology and the
results of preliminary transplantation experiments.
Materials and Methods
The material for the present report is based on 83 cases of adenoma and adeno-
carcinoma of the uterus observed between May, 1934, and December, 1937. In
UTERINE ADENOMATA IN THE RABBIT. I
the majority of cases the tumor was detected during life and its presence subse-
quently confirmed by laparotomy or autopsy. In addition, smaller and micro-
scopic areas of early tumor development were observed during the routine
postmortem examination of other animals. 61 of the tumor bearing animals died
or were killed at various stages of tumor development, 8 died with metastases and
14 are still under observation.
The composition and management of the colony in which the tumors were
found has been described in detail elsewhere (2).
The tumor was transferred to normal animals by the injection of cell emulsions
and the transplantation of tissue fragments. Emulsions were made by grinding
fresh tumor tissue with 0.85 per cent sterile sodium chloride solution and 0.3 cc.
of the mixture was injected at the chosen site. Tissue fragments were selected
from active appearing areas of the tumor and transplanted immediately.
Tumor material was transferred to the subcutaneous tissues, muscle, peritoneal
cavity, testicle and anterior chamber of the eye. Intraocular transfers were
carried out under a local anesthetic. The cornea was punctured at its upper
margin with a corneal knife and a small amount of aqueous humor allowed to
escape. An extremely small tissue fragment of less than 2 ram. in diameter was
then inserted, using forceps with fine serrated points. The best results were
obtained when the tissue was forced into the inferior angle of the iris; this was
easily accomplished by applying pressure along the corneal surface with a blunt
Tissues for microscopic examination were fixed in Petrunkevitch's solution and
stained with hematoxylin and eosin. Pituitary glands were fixed in HeUy's
solution; many were serially sectioned and a variety of stains was used in an at-
tempt to differentiate the various cell types.
The presence of tumor in the uterus of a living animal is not in-
dicated by specific signs or symptoms, and detection of the growth
is dependent upon physical examination.
of all animals has been part of the routine conduct of this colony, and
the majority of tumors have been detected as they became palpable.
It is obvious, however, that the course of the growth is considerably
advanced at the time of discovery.
concerned in this report give no indication of the date of beginning
neoplasia, but analysis shows that disturbances in reproductive func-
tion always precede detection of the tumor and constitute a definite
phase of the disorder.
Preclinical Period.--The fertility and reproductive efficiency of the
colony are under constant check, and it is significant that while the
A systematic examination
The histories of the 83 animals
H. S. N. GREENE AND J. A. SAXTON, JR.
early histories of affected animals were characterized by normal
reproductive activity, a pronounced alteration in fertility, litter size
and maternal care occurred during the period immediately preceding
discovery of the tumor.
Fertility was greatly diminished for 4 to 5 months prior to detection of the
growth. In one group containing approximately one-third of the animals, fertility
ceased abruptly, but the last gestation period was normal in all respects and
terminated in the birth of a litter of usual size which subsequently received good
maternal care. In other animals, the percentage of sterile matings was greatly
increased, but occasional pregnancies resulted, and in 7 instances matings made
within 2 months of tumor detection proved fertile. The litters born to animals
of this group were reduced in size, contained many dead young and desertion by
the mother was common. The reduction in litter size was frequently abrupt with
a diminution to less than one-half of the average number of young; in other
instances the reduction was gradual and became more pronounced as the date of
tumor detection was approached.
Other abnormalities of gestation were common in animals of this group. There
were 3 instances in which whole litters were retained in utero far beyond the limits
of normal gestation and 4 instances of abdominal pregnancy. In addition, there
were 21 cases in which the products of conception were either aborted or resorbed
during the 2nd week of gestation. The usual history in such cases was that
pregnancy was diagnosed 10 days after a mating on the basis of uterine nodules
resembling pregnancy cysts, but delivery failed to occur at the end of an average
gestation period, and subsequent examination revealed an empty uterus.
In general the period of altered reproductive function extended for
4 to 6 months prior to the clinical detection of the tumor.
sistent changes were noted on palpation of the uterus during this
period, but in view of the persistent occurrence of reproductive
abnormalities, it is reasonable to assume the presence of functional
alterations. Moreover, inasmuch as the postmortem discovery of
extremely small tumor nodules not palpable during life, was also
preceded by long periods of reproductive disturbances, it seems prob-
able that the functional alteration may have been present before
the initiation of neoplastic changes.
Period of Growth.--
Detection of the tumor depends on the palpation of uterine nodules which
persist and increase in size. The nodules when first noted, approximate the size
of 10 day pregnancy cysts. They are frequently multiple and may be present in
UTERINE ADENOM-ATA IN THE RABBIT. I
both uterine horns. In such cases their distribution also resembles that of preg-
nancy cysts. The differential diagnosis rests on the firmness, absence of fluctua-
tion and slow growth of the tumor nodules.
The rate of growth varies in different animals. The tumors may reach the size
of hens' eggs in 6 months, or may remain barely palpable for a similar period.
Occasionally, large tumor masses have been found to regress in size, and it is a point
of interest that such an occurrence has been repeatedly observed prior to metas-
tasis. In other instances metastasis has occurred without a palpable increase in
the size of the primary nodules, which have remained no larger than 1.5 cm. in
diameter for more than a year.
In approximately one-quarter of the cases cystic breast changes
were noted when the uterine tumor was first detected. The changes
were either diffuse or limited to a single breast, and on microscopic
examination were similar to those found in chronic cystic disease in
man. Subsequently, definite tumors developed in the affected breasts
of 3 animals. The growth in one instance was a pure adenoma in
type while the tissue changes in the others resembled those of a
fibroadenoma. In one of the latter cases the breast tumor progressed
more rapidly than the uterine and the animal eventually died with
metastases from that growth.
The fertility of tumor bearing animals has been tested in numerous
instances and all matings have proved sterile. Sterilityis apparently
not due to the obstruction caused by the tumor mass, for repeated
matings of animals with small nodules limited to one horn have also
been uniformly infertile.
There are no constant manifestations in the general behavior of
an animal other than those associated with breeding activity to
indicate the presence of tumor. Frequently, during the course of
the tumor, animals exhibit signs generally associated with pregnancy.
The breasts become engorged, the temperamental changes common to
the end of gestation appear and the animals pull fur and build nests.
Similar manifestations have been observed in normal animals during
pseudopregnancy resulting from a sterile mating, but the animals in
question had not been mated for long periods, and it is assumed
that an endocrine disturbance was associated with the presence
of the tumor.
There is no evidence that the tumors are painful and the uterus
may be palpated without apparent tenderness. Bleeding is a rare
FIG. 8. Section of early uterine nodule obtained when the mass first became
clinically palpable. The growth has invaded the wall of a blood vessel and de-
tached tumor cells lie free in the lumen. Hematoxylin and eosin.
FIG. 9. Section of lung showing large metastatic nodule. Hematoxylin and
eosin. X 140.
FIG. 10. Section of thyroid gland showing closely packed acini lined by low
epithelium and an adjacent area containing numerous dilated intercommunicating
glands and a portion of a macroscopic cyst. Hematoxylin and eosin.
Fio. 11. Section of suprarenal. A zone of more or less homogeneous material
entirely separates cortex and medulla. Hematoxylin and eosin.
Fio. 12. Eye showing actively growing transplant in the anterior chamber.
THE JOURNAL OF EXPERIMENTAL MEDICINE VOL. 67 PLATE 30
Photographed by j'. A. Carlile
(Greene and Saxton: Uterine adenomata in the rabbit. I)
FIG. 13. Section of transplanted tumor in the eye resulting from the 2nd serial
transfer. The tissue was obtained by biopsy 2 months after transplantation.
Hematoxylin and eosin. × 67.
FIG. 14. Section of transplanted tumor in the eye resulting from the 6th serial
transfer. The tissue was obtained by biopsy 1½ months after transplantation and
shows a more compact cellular structure. Hematoxylin and eosin.
FIc. 15. Section of transplanted tumor in the testicle resulting from the 2nd
serial intratesticular transfer. The original intratesticular transplant was derived
from the 5th serial eye transfer. The tissue shown in this section was obtained by
biopsy 1¼ months after transplantation. The growth is compact and very
cellular. At one point perivascular spaces have been invaded. Hematoxylin and
eosin. X 68.
FIG. 16. Section of a tumor nodule in a different portion of the same testicle.
Hematoxylin and eosin. × 52.
FIC. 17. High power view of advancing edge of nodule pictured in Fig. 16.
The section shows invasion of the testicular parenchyma with groups and columns
of tumor cells surrounding and destroying tubules. Hematoxylin and eosin.
THE JOURNAL OF EXPERIMENTAL MEDICINE VOL. 67
Photographed by J. A. Carlile
(Greene and Saxton: Uterine adenomata in the rabbit. I)