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Myometrium and leiomyomas in endometrial carcinoma. Failure of involution and reactivation of smooth muscle tissue
MYOMETRIUM AND LEIOMYOMAS IN ENDOMETRIAL FAILURE OF INVOLUTION AND REACTIVATION MUSCLE TISSUE SIEGFRIED TANNHAUSER, (From
the
Departments
M.D., BUFFALO,
of Pathology, the Deaconess Medical
Hospital,
and
CARCINOMA. OF SMOOTH
N. Y. the
University
of Buffalo
School)
T
HE problems dealt with in the forthcoming paper were first encountered when casual and subsequently systematic observations on uteri removed for endometrial. carcinoma showed that on the average their size was considerably This was especially conlarger than normal for the age group of the patients. spicuous in the late postmenopausal phase, in women past 60 years of age, in whom a small and atrophic organ, weighing not more than 30 to 50 grams was to be expected. Instead, often large specimens of two to three times normal weights and measurements were observed. The myometrium, rather than being thin, flabby, rubbery, of a dead grayish-pink, was thick, meaty, turgid, firm, of deep pink or rosy color. On the whole, these uteri looked “youthful,” like premenopausal uteri. Relation
of Size of Carcinoma
to That of the Whole Organ
Naturally the question arose whether this enlargement might not be substantially due to the mass of the tumor present in these uteri. Our observations did not bear this out; the hypertrophy was present with small, incipient carcinomas as well as with advanced ones and the size of the malignant tumor was not in proportional relation to that of the entire specimen. In a few instances relatively large carcinomas were found within small uteri and much more often small carcinomas in large uteri. The same quantitative relations held true for autopsy specimens of endometrial carcinoma. The exact estimation of the relative mass of malignant tumor and surrounding myometrium is extremely difficult if not impossible. As far as possible, quantitative estimations of the relative mass of tumor and myometrium were taken; in infiltrative tumors, especially after radiation, the estimation had to rely upon impression. From our available data it appears that in the great majority of cases the mass of the carcinoma was below one-fifth of the total specimen, often between one-tenth and one-twentieth ; in the irradiated uteri only microscopic traces of tumor of negligible mass were found. The conclusion of these quantitative findings was that the enlargement of the uterus was mainly due to hypertrophy of the myometrium. Microscopic
Studies of the Myometrium
The gross impression of hypertrophy of the myometrium part in our microscopic studies of our material.
found its counter-
266 Muscke ~ibcrs.--Normally. wit 11I I:(> ayproac*h of thct mcno~~a~~, the rnusc:l~ fibers of the myomet,rium start, to sflkrk. bccumin~ thinner with incrtGng quantities of collagenous fibers appearing bctwecn thcut. Stil i la~cr they IU;I> lose their identity completel~~. Often ;I homogeneous maw of collagcnous i~r hyaline fibrous tissue is all that is IcTt l)etwecn n~~lci. 111 cwmeetiw tissue stains this fibrous transforma,tion oi’ tllc, aging uterus is clearly demor~st~rable,
Fig.
2.-Ehdometrial
carcinoma.
vaman
72 muscle
years old. fibers.
Rejuvenation
of
myometrium
:
long
Jn contradistinction, in the pertinent cases of our study, the muscle fibers were a pecxxliarly clearly identifiable, often long, broad, sometimes prmnt-kg luscious aspect, not unlike those of pregnancy. This reactivation or (in
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younger patients, closer to the menopause) failure of involution was clearly distinguished from edematous changes. Where these occurred there resulted a sheetlike blurred picture of swollen collagenous fibers ; small ,lacunae appeared in the hyaline or fibrillar ground substance. The nuclei present in these areas did not show the characteristic changes which will be described later on. In several cases of infiltration of the myometrium by carcinoma of the ovary and in one case by metastatic breast carcinoma there occurred no gross hypertrophy of the myometrium nor microscopic reactivation of the musculature.
Fig.
Fig.
3.-Endcmetrial
4.-Myometrium
carcinoma,
of
woman
woman
69
59 years old. nuclei.
years
old. therapy.
Rejuvenated
Rejuvenation
myometrium
through
: oval
prolonged
vesicular
estrogen
Behavior of Nuclei.-The shape of the involuted myometrial nuclei is elongated, thin, rodlike, sometimes kinked, tortuous, and worm-like. On crosssection they are small, irregularly roundish, bean, or kidney shaped. They stain deeply, like pyknotic nuclei ; the nuclear membrane is thick, the chromatin sometimes clumped. They are usually densely packed due to the lack of fibrillar substance. In the uteri with myometrial hypertr’ophy the nuclei become larger.
In the longitudinal sections they assume an oblong eIIipt.ic or even oval shape, losing their rod-like aspect; in cross .sertions they lose the indented kidney- or hean-shaped contour, becoming perfectly circular. They stain lighter with hematoxylin, the nuclear membrane is thinner. The entire nucleus shows the scanty, spotty chromat,in distribution ~1’vesicular nuclei. Zonal Inequality of Changes.--A peculiar zonal inequality of these changes was sometimes noted. Conspicuously large muscle cells were found around the larger vessels in the periphery of the uterus. Farther inward there followed a zone of lesser cellular changes, of relat.ive quiescence; finally, adjacent, to the lumen and the cacinomatous areas there ensued a broad zone of very marked Fhanges. Cellular Changes in Grossly Yet Enlarged Uteri.----Not all our specimens of carcinomatous uteri were grossly enlarged, approximately 35 per cent showing measurements and weights within the normal limit for the age group. However, even in these uteri, the above-described cellular changes were evident, sometimes in smaller or larger foci separat,ed by quiescent areas. We gained the impression that the first changes in the process of reactivation involved the nuclei at a time when the muscle fibers were still quiescent and hardly identifiable. Behavior of Blood Vessels.--Numerous new, small and large blood vessels were present all through the myometrium. This increase was noted in the myometrium adjacent to t.he carcinoma as well as in areas remote from its site. Reaction of Reactivatecl ATeas With Xpe~ctil Stai?zs.-While most of our :ases were studied with routine hematoxylin-eosin stains, Mallory-Azan and van Gieson stains were also used in a number of selected eases. With both these stains the impression of reactivation of the muscle fibers gained in the routine hematoxylin-eosin preparations was confirmed. Definition of “Rejuvenation. “- The macroscopic and microscopic changes described above resulted in a picture resembling the premenopausal myometrium. Snce these changes were most conspicuous in 1at.e postmenopausal cases the term “ rejuvenation ” was considered most adequate for a comprehensive definition of the entire complex; it will be subsequently used. Influence
of Radiation
on the Size of Uteri and Myometrhl
C’!bages
The most commonly used procedure in treating endometrial carcinoma at present is the intrauterine application of radium, followed after 6 to 8 weeks. ly total hysterectomy. According to the clinical impression of the gyneeoiogists, ;he radium treatment is accompanied by a very marked shrinkage of the uterus, sometimes down to one-half or even less of its original size. In the cases where neasurements of the uterine lumen prior to administration of radium were ;aken, an approximate shrinkage of one-third was noted at the subsequent lysterectomy. These studies are continued at present. How much of this shrinkage is due to regression of the tumor and how much to that of the myonetrium is difficult to estimate and probably varies from case to case. This impression is corroborated by the microscolnc findings in irradiated tnd nonirradiated uteri. Whereas edema and ne
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LeiomyomasPresent in CarcinomatousUteri Our studies revealed that leiomyomas present in the carcinomatous uteri frequently participated in the process of rejuvenation. The natural history of the leiomyoma calls for involution at the menopause, similarly to the myometrium. Even before that time their tendency to undergo hyaline and fibrotic changes often inhibits their further growth. The normal aspect of postmenopausal myomas is that of quiescence; they look grossly and Their cut surface microscopically “ dead, ’ ’ even more so than the myometrium. is smooth. As a rule they are of leathery, sometimes extremely hard, dry consistency; their color is whitish gray. Hyalinization and more or less extensive calcification are common. Their size is of course dependent upon what it was before the menopause, for example, a grapefruit-sized tumor may shrink to the size of a peach and a peach-sized one to that of a cherry. i&roscopically, the same changes as described for the involutional myometrium take place. The cells become small and often scarce, the muscle fibers disappear. Large areas of acellular hyalinization are present; vessels are calcified and often occluded, small vessels and capillaries are extremely scanty.
Fig.
5.-Cellular,
active
leiomyoma
in
~v~rnan
58
years
old
with
endometrial
carcinoma.
The majority of the leiomyomas associated with endometrial carcinomas presented an entirely different picture. In the gross aspect they showed the whorly uneven cut surface of the premenopausal tumors; they were of elastic, resilient, or turgid, sometimes even succulent or edematous, consistency; their color was pinkish in varying shades of depth. As a group they were considerably larger than those found in nonmalignant uteri; they impressed one as actively growing. The microscopic picture corresponded to the gross impression. Some of th.ese leiomyomas were very cellular, even resembling a low-grade sarcoma ; their muscle fibers were comparatively small, the nuclei large and vesicular, mitoses were increased in numbers. The leiomyomas of this type were evidently of recent origin, not reactivated dormant tumors. In this latter type there prevailed a different process. Islands of actively growing muscle cells with long fibers and oval thin-walled nuclei alternated with dormant areas of acellular hyaline tissue, In other areas single young cells with large hyperchromatic nuclei developed within the hyaline tissue, there were also numerous newly formed capillaries lined with cuboidal endothelia. In still other areas of
270 previous homogeneous hyalinization a11 OCR-aL1 breakup of these h>-alintt masstLy by diffusely proliferating muscle cells MXS observed. These cells were tlSulitIl~ seen in small groups, surrounded by lacunary syactx. The still rernailtitlp hyaline tissue formed a. peculiar retic*ulatcd Ilattern tletween these rejurvnarcc! cell groups. Calcifications in these m\;omas show marginal resorpt.ion oi’ tAc%ic granules; there wa,s apposition of ma~ophages at the decalcified fringes ; ilew blood vessels were observed in thri~* irrlltlptliatcl Ilci~:htlor,hood, old oc~luclctl !JIICS were undergoing recanalization.
Fig.
6.-Woman
80 years reticular
old, endcmetrial carcinoma pattern: massing of nucki,
Focus large
of reactivation phagocytes.
in
leiomyoma;
Large cells, with deeply eosinophilic or basophilic cytoplasm and oval nucleus were found in great numbers in and around the lacunary spaces of the rejuvenated myomas. Some of them showed small da.rk-stained eytop&xmic inclusions. In all probability these cells are specialized macrophages, with the task of removal of t,he hyaline matter.
Statistical
Observations
The statistical work-up was undertaken on a material of 1,.153 uteri, removed during the past 5 years. There were 1,095 nonmalignant and 58 m&gnant cases. Twelve additional ut.eri with carcinoma were used only in the first part of the statistical considerations (see below), on account of insua@ient measurements. These considerations divided themselves naturally into two groups : Group I. The percentage of uteri with endometrial carcinoma in which the above-described macroscopic and nticroscopir changes of the myometrial elements were present. Group II. A comparison of weights and measurements between the malignant and nonmalignarit groups of uteri.
Ckoup I.
Percentage
The statistical
Endometrial
work-up
of U~rrch~toue Uteri Wit% RejuveMicm the Iyometrium of this group encountered
caroinoma is xsually
pausiil age group;
of
considerable difficulties.
a disease of the menopeb~&4 -@d p
a certain precentage
of cases will occur before the elin~cally
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271
recognizable menopause. In these latter cases and also in the cases occurring during a transitional period which arbitrarily was set at between 50 and 60 years of age histologically active myometrium may be a normal finding or simply a retardation of the involution as it may occasionally occur, especiaIly in the It may however be stressed that present age of widely used estrogen therapy. in all of them myometrium of premenopausal type was present, whereas in the nonmalignant uteri of the age group between 50 and 60 years only 23 per cent showed premenopausal type myometrium. There remained a group of 14 carcinomatous uteri of women past the age of 60 years. Of these, one with a minute carcinoma which was incidentally detected (the uterus was vaginally removed for prolapse) showed no rejuvenation changes; all the others, 93 per cent 01 this small series, showed various degrees of rejuvenation. Although this group is small, its high percentage of myometrial reactivation fits in with the impression we gained from the studies of the whole malignant group.
Group II.
The Comparison the Malignant
of the Weights and Measurements and the Nonmalignant Groups
Between
This could be undertaken only after previous analytical considerations of all the factors influencing t.he weight and size of the removed uteri. The first consideration was given to different age brackets. The greatest difference in weights was to be expected in the late age group when the normal uterus should On the other hand, in the premenopausal age group this be small and atrophic. difference should be relatively small since the nonmalignant specimens of this group would normally be relatively hi g, their myometrium still active, and enlargement due to myometrial changes in the carcinomatous specimens could be only of minor nature. For these reasons it was thought best to establish four age brackets, a predominantly premenopausal bracket before the age of 50, an early and late transitional bracket between the ages of 50 and 55 years and 55 and 60 years, respectively; a late postmenopausal group of over 60 years. These expectations are borne out by our figures. The smallest percentagewise difference is present in the. youngest age group, the highest in the oldest one, increasing through the translt,lonal groups (Table I). There are some more factors which should be considered with these statistics and which have the effect of intensifying this trend of increasing spread of weight and measurements with higher age. In the nonmalignant. group below 50 years of age, there were a large number of partial hysterectomies, in which the cervix was left in the body. The weight of the cervix in this age group is not inconsiderable, varying between 10 and 30 grams. If this weight were added to the weight of the removed corpus, it would produce a corresponding statistical increase in the weight of On the other hand, the malignant uteri of this the specimens of this group. age group, as well as those of the other age groups, are removed by total hysterectomy, the weight of the cervix already implied in their total weight. Thus, the divergency in weights in the premenopansal age group is in rea1it.y slightly smaller than expressed in our statistics. In the late postmenopausal age group this difference between the weights of the nonleiomyomatous malignant and nonmalignant uteri is in reality greater than apparent from our figures if we consider the fact that most, if not all of these nonmalignant uteri have been removed for prolapse. Due to the elongation of the cervix, these uteri are mostly long and thin ; the largest specimen
72
Am. J. Obsr. & Gym Febwarv.
19i 1
)f this group for instance weighed 105 grams and measured 12 by 3 by 2+” cm. -11 our experience approximately one-t,hirtl to one-half of the weight of these jrolapsed uteri is the weight. of the cervis. Xonyrohqsed uteri of this age group with their extremely small cervices, as for inslance those incidentally uemoved at autopsies, weigh rarely more than 30 grams. Therefore, the rea.1 veight of these uteri without t,he enlarged cervix would be smaller and the jercentual increase of the malignant over the nonmalignant group would be Ggher than our, figures indicate. ___.-
---~. NO MALIGNANCY NO LEIOMYOMA
; / I
lge Group Under 50 Years.Tumber of cases Lverage weight Veigbt range Low High Yeight increase of malignant group lge Group 50-55 Years.slumber of cases Lverage weight Veight range Low High Neight increase of malignant group Ige Group 55-60 Years.qumber of cases Lverage weight Veight range Low High Veight increase of malignant
I-_ / I
327 124 Gm.
..-.
1;; Gm. ___-.-20 Gm. 320 Gm.I
----.~
-;-__ 1” / 12 Gm. _.... ---80 Gm. 320 Gm. ---,
3;;
2::
20 Gm. , -_- T-460 Gm.
1
.-i --
~~-
I 16 I ----420y.--
.- _I 333 320 Gm. _-~-~/~_-~---~-
/ 1 31%
I
--~-.
-
I 1 1 MALIGNANCY / LEIOYYOMA
?W MALI& NANCY IXIOMYOMA
-I14; Gm. -i--&-j : ~~ __._-..-,-. ;
-.- .-_--
/
rmh
20 Gm. i 220 Gm. -i--- 1 -14%
jp
--__-~-.-__-._-.-..
’ j MALIGNANCY ; SO LFXOMY-
60
Gm.
1220
Gim. -- .-
467* Gm. -_- _l_.--
-.., ___.-20 Gm. 1460~~~--Gm.
7()%
60 Gm. 1220 --.---am.
31% I /
~~~- ^-.
22 90 Gm.
7 140
Gm.
i
30 Gm. 240 Gm. - ------?zyO
-.-----..-
’
60 Gm. 180 Gm.
ZKUD
lge Group Over 60 Years.Tumber of cases 6 / 34 -A-iverage weight 55 Gm. -I 90 Gm. -.IYeight range Low 20 Gm. High 120 Gm. j ~~1: Et Veight increase of malignant, 64% group ---______----
; __.
30 Gm. 480 Gm. --. .~-------
-
---I__- 208 I
j j 73%
Gm.
80 Gm. 46Q Urn.
!
__-.-__ “5 260
Gm.
3 450 Gm.
40 Gm. 200 Gm.
80 Gm. 1100 --~ Gm. 7
%$As stated before, it follows from our graphs and from the consideratkms )f these factors in the youngest, and on the other hand in t,he oldest age group #hat the higher the age, the greater the percentual weighty increase of the maligrant over the nonmalignant uterus. Besides the data presented in Table I we also charted incidence of adenomyosis and previous radiation. These a&Ii&ma1 Data helped in analyzing cases, which appeared to fall out of the normal. for ;heir age-weight group ; i.e. the snrp4singly high weight of Ik# gztra- in a roncancerous uterus of a woman 60 years old was expb&ned by the presence of t large area of regressing adenomyosis.
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Remarks Concerningthe Individual Groups We realize that the case numb,er of our malignant material is too small to allow too close a statistical breakdown. It should however be of some significance that not only is the average weight of the malignant groups higher than that of the nonmalignant ones, but that throughout all charts the weight of the smallest malignant specimen is greater than the weight of the corresponding nonmalignant one and that the same is true of the largest specimens of each group. Another clinically important conclusion of our figures is that in the age group above 60 years, if specimens with leiomyomas, adenomyosis, and prolapse are discounted, all uteri over 60 to 70 grams of weight show malignancy.
Findings in Sarcomas The same changes as with carcinomas were in evidence in the myometrium of uteri with leiomyosarcoma. Furthermore, in the few cases observed in the late postmenopausal stage, marked endometrial hpperplasia accompanied the sarcomat,ous myometrial changes.
Referencesin the Literature As far as a careful study of the pertinent literature of the last 15 years and examination of older textbooks on pathology and gynecology could reveal, the complex of the present investigation has not been systematically covered before. Actually, the onlv reference which could be found at all is a short remark of Robert Meyer1 in Henke-Lnbarsrh’s Handbook of Pathology, citing Theilhaber and Hollinger,2 “ that sometimes hypert.rophy of the myometrium accompanies endometrial carcinoma, mostly as independent myohyperplasia, not as a consequence of work-hypertrophy. ” In the numerous papers on carcinoma and leiomyoma no systematic correlation of the size of the uterus and that of the myomas was made nor was their histology a subject of investigation except for the paper of Tibirica” describing the co-existence of a malignant fibromyoma and of adenocarcinoma of the uterus.
Pathogenetic Correlations The findings of our study on myometrial reactivation and hypertrophy accompanying endometrial carcinoma appear to contribute more support to the theory of hormonal causation of endometrial carcinomas. We find in our own material actual proof that estrogenic hormones may affect both myometrium and endometrium. The histology of several uteri removed following energetic estrogenic therapy shows that both myometrium and endometrium react, the myometrium with rejuvenation, the endometrium with hyperplasia. The same concomitant reaction of both endometrium and myometrium was observed in two cases of thecoma of the ovary, one of which showed fully developed carcinoma, the other one massive adenomatous hyperplasia of the endometrium. In another case of carcinoma of t,he endometrium accompanied by marked myometrial rejuvenation, peculiar adrenal-like cell masses were found in the hilus region of the ovary. The role of estrogenic hormones in proliferative processes of the postmenopausal endometrium has been well established by the reports of endometrial hyperplasia and even carcinoma following estrogen t.herapy, on the one hand, and endometrial carcinoma accompanying theca cell tumors, on the other hand.5l 6y7, s, g While Novak4 and ZondeklO both believe that there is no conclusive evidence of uterine cancer caused by estrogen therapy, there are re-
ports by Vass’” and M. Fremont Smith and asyociatrs’- 01’ carrilloma of the c-Clo I-lemf~l” Il;ts IlrTer sccll (~R~f’illOll~i;l Of metrium following this type of thtwtI~y. the endometrium after oophorectomJ7 in 841 ~RSPS. While thus there is on the whole :i mounting amount of indication of the role of endocrine factors, especially Of ovarian origin ill the causation of endornetrial benign and malignant prolii’erative processes, t,llc question arises whercb the production of these hormones takes pla,ce in tlttk I)ostmeno7,ausal ovaries without thecoma or granulosa-cell tumors. Shaw and associates’.’ found pcculial endocrinoid cells in the ovarian hilnnl in 2-l out of -8 cases of endomctrial ~,denocarcinoma. They hold that the-se cells ~~robabl~- originate frum the endothelium of small capillaries or lymphxtics since they were inva,riably found in the ‘neighborhood of blood vessels. They denied the possibilities t,hat their cells are identical with the hilum cells which are clrszribcd in the paper of Sternberg.‘” as consisting The st,rurture of the ovariatl S~IY~III:~itself ~OII:! f~o~lsi4lcrrd :Jf connective tissue-like elements has l:ltrl?- I)er~r the 5ul)ject of’ several studies I’ovak” points 1o resulting in a substantial revision elf this illtelpl.‘,t~~tiotl. ;he possible influencar of stromal hyl)tJrplasia on the spont,aneous postmclloSchwa.rz and TI’oung. Ii itI a dealing with this Iiispausal hyperplasia. tology and development of the o\-;lri;lIl stro111;t. nw of the ol)imion that the :ells of the ova.rian stroma arc cle1*i\-rtl from the vaseul~ar walls and, judging show Tnuch JIIOIT t-he from their morphologic and st,aininr characteristics. properties of smooth muscle than of c*onnectirr tissue. DeC:iorgi’” stresses the structural similarity of the uvari;tn struma tct f~rrt~tile tissue. Woll and ~ssociatesl” found stromal hvpcq)lasi;t of the ovary irt 56 to 92 per cent of . zases of carcinoma of the uterus, whcrras in ~OJI~J~OI groups this hyperplasia was present in 36 to 42 per cent. In a preliminary surrey of the o\xries removed together with carcinomatous uteri we too galnet the impression that the degree of stromal hyperplasia was larger than in t,he control cases. However, this impression needs furt,hel systematic studlrs corroboratefl by c~oltnrct ivc tissue ilIlf? fat stains for future evaluation. IJilpt'l
Clinical Significance Aside from the theoretical aspccl of the problem, its practic*al c*linicitI side should also he stressed. A nonprolapsed uterus of the late postlllenolraus;ll sge group which is distinctly larger than normal should by its size alone arouse suspicion of intrinsic rnaiig-nancy or else c~f ;I horn~one-protiu~~ing The same is true of n~yon~as which show signs of reactivation avarian tumor. such as growt.h, pain, or soft, meaty ~ousistcncy on palpation. It seems possible that increased clinical consciousness of these factors may in suitable zases lead to the diagnosis of Iualignauc~y iti earlier a~~1 more favorable stages. summary Gross and histologic studies on #58 uteri with endometrial carcinoma showed in a great percentage of cases failure of involution or reactivation If the myometrium (rejuvenation j Leiomyomas present in uteri jvith endometrial carcinomas showed similar changes, leading to enlargement ant1 reactivation of formerly dormant tumors. Statistical comparison of malignant and nonmalignant uteri demonstrated higher weights in the former group, the weight difference percentagewise
mcreasing with age.
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The pa.thogenetic significance of t,hese findings is discussed and correlated with findings of the literature and of our own observations supporting the view of a hormonal impact hitting the uterus in its totality, sometimes leading only to late endometrial hyperplasia, in other cases to carcinoma or sarcoma accompanied by myometrial hyperplasia. The significance of these studies for ;I possible earlier clinical recognition of endometrial carcinoma is stressed.
References Handbuch der spez. path. Anat. II. Histol., Robert: In Henke-Lubarsch: Berlin, 1937, Julius Springer, vol. 7, p. 501. Meyer, Robert:1 Tibiriea, P. Q. T.: Ann. paulist, de med. cir. 40: 193, 1940. Novak, Emil: Gynecological and Obstetrical Pathology, ed. 2, Baltimore, 1947, W. B. Saunders Company, p. 161. Dockerty, M. B.: AM. J. OBST. & GYNEC. 39: 433, 1940. Stohr, G.: AM. J. OBST. & GYNEC. 43: 586, 1942. Ingraham, C. B., Black, W. C., and Rutledge, E. Ii.: AM. J. OBST. & GYNEC. 48: 760, 1944. Kirshbaum, S. D. : AM. J. OBST. 6i GYNEC. 46: 573, 1943. Novak, Emil: Gynecological and Obstetrical Pathology, ed. 2: Baltimore, 1947, W. B. SaundBrs Company, pp. 405, 161. Zondek, B.: Act. Radiol. Scandinav. 28: 433, 1947. Novak, Emil: J. A. M. A. 135: 199, 1947. Herrell, W. E.: AM. J. OBST. & GYNEC. 37: 555, 1939. Vass, A.: AM. J. OBST. & GYNEC. 58: 748, 1949. Smith, M. Fremont, Meigs, J. V.! Graham, R. M., and Gilbert, H. H.: J. A. M. A. 131: 805, 1946. Shaw, Wilfred, and Dastur, R.: Brit. M. J. 2: 113, 1949. Quoted in Year Book of Obstetrics and Gynecology, Chicago, 1949, The Year Book Publishers, p. 532. Sternberg, W. H.: Am. J. Path. 25: 493, 1949. Schwarz, Otto H., and Young, Claude C.: AM. J. OBST. & GYNEC. 59: 84, 1950. DiGiorgi, L.: Cited by Schwarz & Young.17 Woll, E., Hertig, A. T., Smith, G. V. S., and Johnson, L. C.: AM. J. 0~s~. & GYNEC. 56: 617, 1948. Kelly, Howard A.: Operative Gynecology, New York, 1898, D. Appleton & Company.
1. Meyer, 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
the
Departments
M.D., BUFFALO,
of Pathology, the Deaconess Medical
Hospital,
and
CARCINOMA. OF SMOOTH
N. Y. the
University
of Buffalo
School)
T
HE problems dealt with in the forthcoming paper were first encountered when casual and subsequently systematic observations on uteri removed for endometrial. carcinoma showed that on the average their size was considerably This was especially conlarger than normal for the age group of the patients. spicuous in the late postmenopausal phase, in women past 60 years of age, in whom a small and atrophic organ, weighing not more than 30 to 50 grams was to be expected. Instead, often large specimens of two to three times normal weights and measurements were observed. The myometrium, rather than being thin, flabby, rubbery, of a dead grayish-pink, was thick, meaty, turgid, firm, of deep pink or rosy color. On the whole, these uteri looked “youthful,” like premenopausal uteri. Relation
of Size of Carcinoma
to That of the Whole Organ
Naturally the question arose whether this enlargement might not be substantially due to the mass of the tumor present in these uteri. Our observations did not bear this out; the hypertrophy was present with small, incipient carcinomas as well as with advanced ones and the size of the malignant tumor was not in proportional relation to that of the entire specimen. In a few instances relatively large carcinomas were found within small uteri and much more often small carcinomas in large uteri. The same quantitative relations held true for autopsy specimens of endometrial carcinoma. The exact estimation of the relative mass of malignant tumor and surrounding myometrium is extremely difficult if not impossible. As far as possible, quantitative estimations of the relative mass of tumor and myometrium were taken; in infiltrative tumors, especially after radiation, the estimation had to rely upon impression. From our available data it appears that in the great majority of cases the mass of the carcinoma was below one-fifth of the total specimen, often between one-tenth and one-twentieth ; in the irradiated uteri only microscopic traces of tumor of negligible mass were found. The conclusion of these quantitative findings was that the enlargement of the uterus was mainly due to hypertrophy of the myometrium. Microscopic
Studies of the Myometrium
The gross impression of hypertrophy of the myometrium part in our microscopic studies of our material.
found its counter-
266 Muscke ~ibcrs.--Normally. wit 11I I:(> ayproac*h of thct mcno~~a~~, the rnusc:l~ fibers of the myomet,rium start, to sflkrk. bccumin~ thinner with incrtGng quantities of collagenous fibers appearing bctwecn thcut. Stil i la~cr they IU;I> lose their identity completel~~. Often ;I homogeneous maw of collagcnous i~r hyaline fibrous tissue is all that is IcTt l)etwecn n~~lci. 111 cwmeetiw tissue stains this fibrous transforma,tion oi’ tllc, aging uterus is clearly demor~st~rable,
Fig.
2.-Ehdometrial
carcinoma.
vaman
72 muscle
years old. fibers.
Rejuvenation
of
myometrium
:
long
Jn contradistinction, in the pertinent cases of our study, the muscle fibers were a pecxxliarly clearly identifiable, often long, broad, sometimes prmnt-kg luscious aspect, not unlike those of pregnancy. This reactivation or (in
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younger patients, closer to the menopause) failure of involution was clearly distinguished from edematous changes. Where these occurred there resulted a sheetlike blurred picture of swollen collagenous fibers ; small ,lacunae appeared in the hyaline or fibrillar ground substance. The nuclei present in these areas did not show the characteristic changes which will be described later on. In several cases of infiltration of the myometrium by carcinoma of the ovary and in one case by metastatic breast carcinoma there occurred no gross hypertrophy of the myometrium nor microscopic reactivation of the musculature.
Fig.
Fig.
3.-Endcmetrial
4.-Myometrium
carcinoma,
of
woman
woman
69
59 years old. nuclei.
years
old. therapy.
Rejuvenated
Rejuvenation
myometrium
through
: oval
prolonged
vesicular
estrogen
Behavior of Nuclei.-The shape of the involuted myometrial nuclei is elongated, thin, rodlike, sometimes kinked, tortuous, and worm-like. On crosssection they are small, irregularly roundish, bean, or kidney shaped. They stain deeply, like pyknotic nuclei ; the nuclear membrane is thick, the chromatin sometimes clumped. They are usually densely packed due to the lack of fibrillar substance. In the uteri with myometrial hypertr’ophy the nuclei become larger.
In the longitudinal sections they assume an oblong eIIipt.ic or even oval shape, losing their rod-like aspect; in cross .sertions they lose the indented kidney- or hean-shaped contour, becoming perfectly circular. They stain lighter with hematoxylin, the nuclear membrane is thinner. The entire nucleus shows the scanty, spotty chromat,in distribution ~1’vesicular nuclei. Zonal Inequality of Changes.--A peculiar zonal inequality of these changes was sometimes noted. Conspicuously large muscle cells were found around the larger vessels in the periphery of the uterus. Farther inward there followed a zone of lesser cellular changes, of relat.ive quiescence; finally, adjacent, to the lumen and the cacinomatous areas there ensued a broad zone of very marked Fhanges. Cellular Changes in Grossly Yet Enlarged Uteri.----Not all our specimens of carcinomatous uteri were grossly enlarged, approximately 35 per cent showing measurements and weights within the normal limit for the age group. However, even in these uteri, the above-described cellular changes were evident, sometimes in smaller or larger foci separat,ed by quiescent areas. We gained the impression that the first changes in the process of reactivation involved the nuclei at a time when the muscle fibers were still quiescent and hardly identifiable. Behavior of Blood Vessels.--Numerous new, small and large blood vessels were present all through the myometrium. This increase was noted in the myometrium adjacent to t.he carcinoma as well as in areas remote from its site. Reaction of Reactivatecl ATeas With Xpe~ctil Stai?zs.-While most of our :ases were studied with routine hematoxylin-eosin stains, Mallory-Azan and van Gieson stains were also used in a number of selected eases. With both these stains the impression of reactivation of the muscle fibers gained in the routine hematoxylin-eosin preparations was confirmed. Definition of “Rejuvenation. “- The macroscopic and microscopic changes described above resulted in a picture resembling the premenopausal myometrium. Snce these changes were most conspicuous in 1at.e postmenopausal cases the term “ rejuvenation ” was considered most adequate for a comprehensive definition of the entire complex; it will be subsequently used. Influence
of Radiation
on the Size of Uteri and Myometrhl
C’!bages
The most commonly used procedure in treating endometrial carcinoma at present is the intrauterine application of radium, followed after 6 to 8 weeks. ly total hysterectomy. According to the clinical impression of the gyneeoiogists, ;he radium treatment is accompanied by a very marked shrinkage of the uterus, sometimes down to one-half or even less of its original size. In the cases where neasurements of the uterine lumen prior to administration of radium were ;aken, an approximate shrinkage of one-third was noted at the subsequent lysterectomy. These studies are continued at present. How much of this shrinkage is due to regression of the tumor and how much to that of the myonetrium is difficult to estimate and probably varies from case to case. This impression is corroborated by the microscolnc findings in irradiated tnd nonirradiated uteri. Whereas edema and ne
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LeiomyomasPresent in CarcinomatousUteri Our studies revealed that leiomyomas present in the carcinomatous uteri frequently participated in the process of rejuvenation. The natural history of the leiomyoma calls for involution at the menopause, similarly to the myometrium. Even before that time their tendency to undergo hyaline and fibrotic changes often inhibits their further growth. The normal aspect of postmenopausal myomas is that of quiescence; they look grossly and Their cut surface microscopically “ dead, ’ ’ even more so than the myometrium. is smooth. As a rule they are of leathery, sometimes extremely hard, dry consistency; their color is whitish gray. Hyalinization and more or less extensive calcification are common. Their size is of course dependent upon what it was before the menopause, for example, a grapefruit-sized tumor may shrink to the size of a peach and a peach-sized one to that of a cherry. i&roscopically, the same changes as described for the involutional myometrium take place. The cells become small and often scarce, the muscle fibers disappear. Large areas of acellular hyalinization are present; vessels are calcified and often occluded, small vessels and capillaries are extremely scanty.
Fig.
5.-Cellular,
active
leiomyoma
in
~v~rnan
58
years
old
with
endometrial
carcinoma.
The majority of the leiomyomas associated with endometrial carcinomas presented an entirely different picture. In the gross aspect they showed the whorly uneven cut surface of the premenopausal tumors; they were of elastic, resilient, or turgid, sometimes even succulent or edematous, consistency; their color was pinkish in varying shades of depth. As a group they were considerably larger than those found in nonmalignant uteri; they impressed one as actively growing. The microscopic picture corresponded to the gross impression. Some of th.ese leiomyomas were very cellular, even resembling a low-grade sarcoma ; their muscle fibers were comparatively small, the nuclei large and vesicular, mitoses were increased in numbers. The leiomyomas of this type were evidently of recent origin, not reactivated dormant tumors. In this latter type there prevailed a different process. Islands of actively growing muscle cells with long fibers and oval thin-walled nuclei alternated with dormant areas of acellular hyaline tissue, In other areas single young cells with large hyperchromatic nuclei developed within the hyaline tissue, there were also numerous newly formed capillaries lined with cuboidal endothelia. In still other areas of
270 previous homogeneous hyalinization a11 OCR-aL1 breakup of these h>-alintt masstLy by diffusely proliferating muscle cells MXS observed. These cells were tlSulitIl~ seen in small groups, surrounded by lacunary syactx. The still rernailtitlp hyaline tissue formed a. peculiar retic*ulatcd Ilattern tletween these rejurvnarcc! cell groups. Calcifications in these m\;omas show marginal resorpt.ion oi’ tAc%ic granules; there wa,s apposition of ma~ophages at the decalcified fringes ; ilew blood vessels were observed in thri~* irrlltlptliatcl Ilci~:htlor,hood, old oc~luclctl !JIICS were undergoing recanalization.
Fig.
6.-Woman
80 years reticular
old, endcmetrial carcinoma pattern: massing of nucki,
Focus large
of reactivation phagocytes.
in
leiomyoma;
Large cells, with deeply eosinophilic or basophilic cytoplasm and oval nucleus were found in great numbers in and around the lacunary spaces of the rejuvenated myomas. Some of them showed small da.rk-stained eytop&xmic inclusions. In all probability these cells are specialized macrophages, with the task of removal of t,he hyaline matter.
Statistical
Observations
The statistical work-up was undertaken on a material of 1,.153 uteri, removed during the past 5 years. There were 1,095 nonmalignant and 58 m&gnant cases. Twelve additional ut.eri with carcinoma were used only in the first part of the statistical considerations (see below), on account of insua@ient measurements. These considerations divided themselves naturally into two groups : Group I. The percentage of uteri with endometrial carcinoma in which the above-described macroscopic and nticroscopir changes of the myometrial elements were present. Group II. A comparison of weights and measurements between the malignant and nonmalignarit groups of uteri.
Ckoup I.
Percentage
The statistical
Endometrial
work-up
of U~rrch~toue Uteri Wit% RejuveMicm the Iyometrium of this group encountered
caroinoma is xsually
pausiil age group;
of
considerable difficulties.
a disease of the menopeb~&4 -@d p
a certain precentage
of cases will occur before the elin~cally
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recognizable menopause. In these latter cases and also in the cases occurring during a transitional period which arbitrarily was set at between 50 and 60 years of age histologically active myometrium may be a normal finding or simply a retardation of the involution as it may occasionally occur, especiaIly in the It may however be stressed that present age of widely used estrogen therapy. in all of them myometrium of premenopausal type was present, whereas in the nonmalignant uteri of the age group between 50 and 60 years only 23 per cent showed premenopausal type myometrium. There remained a group of 14 carcinomatous uteri of women past the age of 60 years. Of these, one with a minute carcinoma which was incidentally detected (the uterus was vaginally removed for prolapse) showed no rejuvenation changes; all the others, 93 per cent 01 this small series, showed various degrees of rejuvenation. Although this group is small, its high percentage of myometrial reactivation fits in with the impression we gained from the studies of the whole malignant group.
Group II.
The Comparison the Malignant
of the Weights and Measurements and the Nonmalignant Groups
Between
This could be undertaken only after previous analytical considerations of all the factors influencing t.he weight and size of the removed uteri. The first consideration was given to different age brackets. The greatest difference in weights was to be expected in the late age group when the normal uterus should On the other hand, in the premenopausal age group this be small and atrophic. difference should be relatively small since the nonmalignant specimens of this group would normally be relatively hi g, their myometrium still active, and enlargement due to myometrial changes in the carcinomatous specimens could be only of minor nature. For these reasons it was thought best to establish four age brackets, a predominantly premenopausal bracket before the age of 50, an early and late transitional bracket between the ages of 50 and 55 years and 55 and 60 years, respectively; a late postmenopausal group of over 60 years. These expectations are borne out by our figures. The smallest percentagewise difference is present in the. youngest age group, the highest in the oldest one, increasing through the translt,lonal groups (Table I). There are some more factors which should be considered with these statistics and which have the effect of intensifying this trend of increasing spread of weight and measurements with higher age. In the nonmalignant. group below 50 years of age, there were a large number of partial hysterectomies, in which the cervix was left in the body. The weight of the cervix in this age group is not inconsiderable, varying between 10 and 30 grams. If this weight were added to the weight of the removed corpus, it would produce a corresponding statistical increase in the weight of On the other hand, the malignant uteri of this the specimens of this group. age group, as well as those of the other age groups, are removed by total hysterectomy, the weight of the cervix already implied in their total weight. Thus, the divergency in weights in the premenopansal age group is in rea1it.y slightly smaller than expressed in our statistics. In the late postmenopausal age group this difference between the weights of the nonleiomyomatous malignant and nonmalignant uteri is in reality greater than apparent from our figures if we consider the fact that most, if not all of these nonmalignant uteri have been removed for prolapse. Due to the elongation of the cervix, these uteri are mostly long and thin ; the largest specimen
72
Am. J. Obsr. & Gym Febwarv.
19i 1
)f this group for instance weighed 105 grams and measured 12 by 3 by 2+” cm. -11 our experience approximately one-t,hirtl to one-half of the weight of these jrolapsed uteri is the weight. of the cervis. Xonyrohqsed uteri of this age group with their extremely small cervices, as for inslance those incidentally uemoved at autopsies, weigh rarely more than 30 grams. Therefore, the rea.1 veight of these uteri without t,he enlarged cervix would be smaller and the jercentual increase of the malignant over the nonmalignant group would be Ggher than our, figures indicate. ___.-
---~. NO MALIGNANCY NO LEIOMYOMA
; / I
lge Group Under 50 Years.Tumber of cases Lverage weight Veigbt range Low High Yeight increase of malignant group lge Group 50-55 Years.slumber of cases Lverage weight Veight range Low High Neight increase of malignant group Ige Group 55-60 Years.qumber of cases Lverage weight Veight range Low High Veight increase of malignant
I-_ / I
327 124 Gm.
..-.
1;; Gm. ___-.-20 Gm. 320 Gm.I
----.~
-;-__ 1” / 12 Gm. _.... ---80 Gm. 320 Gm. ---,
3;;
2::
20 Gm. , -_- T-460 Gm.
1
.-i --
~~-
I 16 I ----420y.--
.- _I 333 320 Gm. _-~-~/~_-~---~-
/ 1 31%
I
--~-.
-
I 1 1 MALIGNANCY / LEIOYYOMA
?W MALI& NANCY IXIOMYOMA
-I14; Gm. -i--&-j : ~~ __._-..-,-. ;
-.- .-_--
/
rmh
20 Gm. i 220 Gm. -i--- 1 -14%
jp
--__-~-.-__-._-.-..
’ j MALIGNANCY ; SO LFXOMY-
60
Gm.
1220
Gim. -- .-
467* Gm. -_- _l_.--
-.., ___.-20 Gm. 1460~~~--Gm.
7()%
60 Gm. 1220 --.---am.
31% I /
~~~- ^-.
22 90 Gm.
7 140
Gm.
i
30 Gm. 240 Gm. - ------?zyO
-.-----..-
’
60 Gm. 180 Gm.
ZKUD
lge Group Over 60 Years.Tumber of cases 6 / 34 -A-iverage weight 55 Gm. -I 90 Gm. -.IYeight range Low 20 Gm. High 120 Gm. j ~~1: Et Veight increase of malignant, 64% group ---______----
; __.
30 Gm. 480 Gm. --. .~-------
-
---I__- 208 I
j j 73%
Gm.
80 Gm. 46Q Urn.
!
__-.-__ “5 260
Gm.
3 450 Gm.
40 Gm. 200 Gm.
80 Gm. 1100 --~ Gm. 7
%$As stated before, it follows from our graphs and from the consideratkms )f these factors in the youngest, and on the other hand in t,he oldest age group #hat the higher the age, the greater the percentual weighty increase of the maligrant over the nonmalignant uterus. Besides the data presented in Table I we also charted incidence of adenomyosis and previous radiation. These a&Ii&ma1 Data helped in analyzing cases, which appeared to fall out of the normal. for ;heir age-weight group ; i.e. the snrp4singly high weight of Ik# gztra- in a roncancerous uterus of a woman 60 years old was expb&ned by the presence of t large area of regressing adenomyosis.
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273
Remarks Concerningthe Individual Groups We realize that the case numb,er of our malignant material is too small to allow too close a statistical breakdown. It should however be of some significance that not only is the average weight of the malignant groups higher than that of the nonmalignant ones, but that throughout all charts the weight of the smallest malignant specimen is greater than the weight of the corresponding nonmalignant one and that the same is true of the largest specimens of each group. Another clinically important conclusion of our figures is that in the age group above 60 years, if specimens with leiomyomas, adenomyosis, and prolapse are discounted, all uteri over 60 to 70 grams of weight show malignancy.
Findings in Sarcomas The same changes as with carcinomas were in evidence in the myometrium of uteri with leiomyosarcoma. Furthermore, in the few cases observed in the late postmenopausal stage, marked endometrial hpperplasia accompanied the sarcomat,ous myometrial changes.
Referencesin the Literature As far as a careful study of the pertinent literature of the last 15 years and examination of older textbooks on pathology and gynecology could reveal, the complex of the present investigation has not been systematically covered before. Actually, the onlv reference which could be found at all is a short remark of Robert Meyer1 in Henke-Lnbarsrh’s Handbook of Pathology, citing Theilhaber and Hollinger,2 “ that sometimes hypert.rophy of the myometrium accompanies endometrial carcinoma, mostly as independent myohyperplasia, not as a consequence of work-hypertrophy. ” In the numerous papers on carcinoma and leiomyoma no systematic correlation of the size of the uterus and that of the myomas was made nor was their histology a subject of investigation except for the paper of Tibirica” describing the co-existence of a malignant fibromyoma and of adenocarcinoma of the uterus.
Pathogenetic Correlations The findings of our study on myometrial reactivation and hypertrophy accompanying endometrial carcinoma appear to contribute more support to the theory of hormonal causation of endometrial carcinomas. We find in our own material actual proof that estrogenic hormones may affect both myometrium and endometrium. The histology of several uteri removed following energetic estrogenic therapy shows that both myometrium and endometrium react, the myometrium with rejuvenation, the endometrium with hyperplasia. The same concomitant reaction of both endometrium and myometrium was observed in two cases of thecoma of the ovary, one of which showed fully developed carcinoma, the other one massive adenomatous hyperplasia of the endometrium. In another case of carcinoma of t,he endometrium accompanied by marked myometrial rejuvenation, peculiar adrenal-like cell masses were found in the hilus region of the ovary. The role of estrogenic hormones in proliferative processes of the postmenopausal endometrium has been well established by the reports of endometrial hyperplasia and even carcinoma following estrogen t.herapy, on the one hand, and endometrial carcinoma accompanying theca cell tumors, on the other hand.5l 6y7, s, g While Novak4 and ZondeklO both believe that there is no conclusive evidence of uterine cancer caused by estrogen therapy, there are re-
ports by Vass’” and M. Fremont Smith and asyociatrs’- 01’ carrilloma of the c-Clo I-lemf~l” Il;ts IlrTer sccll (~R~f’illOll~i;l Of metrium following this type of thtwtI~y. the endometrium after oophorectomJ7 in 841 ~RSPS. While thus there is on the whole :i mounting amount of indication of the role of endocrine factors, especially Of ovarian origin ill the causation of endornetrial benign and malignant prolii’erative processes, t,llc question arises whercb the production of these hormones takes pla,ce in tlttk I)ostmeno7,ausal ovaries without thecoma or granulosa-cell tumors. Shaw and associates’.’ found pcculial endocrinoid cells in the ovarian hilnnl in 2-l out of -8 cases of endomctrial ~,denocarcinoma. They hold that the-se cells ~~robabl~- originate frum the endothelium of small capillaries or lymphxtics since they were inva,riably found in the ‘neighborhood of blood vessels. They denied the possibilities t,hat their cells are identical with the hilum cells which are clrszribcd in the paper of Sternberg.‘” as consisting The st,rurture of the ovariatl S~IY~III:~itself ~OII:! f~o~lsi4lcrrd :Jf connective tissue-like elements has l:ltrl?- I)er~r the 5ul)ject of’ several studies I’ovak” points 1o resulting in a substantial revision elf this illtelpl.‘,t~~tiotl. ;he possible influencar of stromal hyl)tJrplasia on the spont,aneous postmclloSchwa.rz and TI’oung. Ii itI a dealing with this Iiispausal hyperplasia. tology and development of the o\-;lri;lIl stro111;t. nw of the ol)imion that the :ells of the ova.rian stroma arc cle1*i\-rtl from the vaseul~ar walls and, judging show Tnuch JIIOIT t-he from their morphologic and st,aininr characteristics. properties of smooth muscle than of c*onnectirr tissue. DeC:iorgi’” stresses the structural similarity of the uvari;tn struma tct f~rrt~tile tissue. Woll and ~ssociatesl” found stromal hvpcq)lasi;t of the ovary irt 56 to 92 per cent of . zases of carcinoma of the uterus, whcrras in ~OJI~J~OI groups this hyperplasia was present in 36 to 42 per cent. In a preliminary surrey of the o\xries removed together with carcinomatous uteri we too galnet the impression that the degree of stromal hyperplasia was larger than in t,he control cases. However, this impression needs furt,hel systematic studlrs corroboratefl by c~oltnrct ivc tissue ilIlf? fat stains for future evaluation. IJilpt'l
Clinical Significance Aside from the theoretical aspccl of the problem, its practic*al c*linicitI side should also he stressed. A nonprolapsed uterus of the late postlllenolraus;ll sge group which is distinctly larger than normal should by its size alone arouse suspicion of intrinsic rnaiig-nancy or else c~f ;I horn~one-protiu~~ing The same is true of n~yon~as which show signs of reactivation avarian tumor. such as growt.h, pain, or soft, meaty ~ousistcncy on palpation. It seems possible that increased clinical consciousness of these factors may in suitable zases lead to the diagnosis of Iualignauc~y iti earlier a~~1 more favorable stages. summary Gross and histologic studies on #58 uteri with endometrial carcinoma showed in a great percentage of cases failure of involution or reactivation If the myometrium (rejuvenation j Leiomyomas present in uteri jvith endometrial carcinomas showed similar changes, leading to enlargement ant1 reactivation of formerly dormant tumors. Statistical comparison of malignant and nonmalignant uteri demonstrated higher weights in the former group, the weight difference percentagewise
mcreasing with age.
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The pa.thogenetic significance of t,hese findings is discussed and correlated with findings of the literature and of our own observations supporting the view of a hormonal impact hitting the uterus in its totality, sometimes leading only to late endometrial hyperplasia, in other cases to carcinoma or sarcoma accompanied by myometrial hyperplasia. The significance of these studies for ;I possible earlier clinical recognition of endometrial carcinoma is stressed.
References Handbuch der spez. path. Anat. II. Histol., Robert: In Henke-Lubarsch: Berlin, 1937, Julius Springer, vol. 7, p. 501. Meyer, Robert:1 Tibiriea, P. Q. T.: Ann. paulist, de med. cir. 40: 193, 1940. Novak, Emil: Gynecological and Obstetrical Pathology, ed. 2, Baltimore, 1947, W. B. Saunders Company, p. 161. Dockerty, M. B.: AM. J. OBST. & GYNEC. 39: 433, 1940. Stohr, G.: AM. J. OBST. & GYNEC. 43: 586, 1942. Ingraham, C. B., Black, W. C., and Rutledge, E. Ii.: AM. J. OBST. & GYNEC. 48: 760, 1944. Kirshbaum, S. D. : AM. J. OBST. 6i GYNEC. 46: 573, 1943. Novak, Emil: Gynecological and Obstetrical Pathology, ed. 2: Baltimore, 1947, W. B. SaundBrs Company, pp. 405, 161. Zondek, B.: Act. Radiol. Scandinav. 28: 433, 1947. Novak, Emil: J. A. M. A. 135: 199, 1947. Herrell, W. E.: AM. J. OBST. & GYNEC. 37: 555, 1939. Vass, A.: AM. J. OBST. & GYNEC. 58: 748, 1949. Smith, M. Fremont, Meigs, J. V.! Graham, R. M., and Gilbert, H. H.: J. A. M. A. 131: 805, 1946. Shaw, Wilfred, and Dastur, R.: Brit. M. J. 2: 113, 1949. Quoted in Year Book of Obstetrics and Gynecology, Chicago, 1949, The Year Book Publishers, p. 532. Sternberg, W. H.: Am. J. Path. 25: 493, 1949. Schwarz, Otto H., and Young, Claude C.: AM. J. OBST. & GYNEC. 59: 84, 1950. DiGiorgi, L.: Cited by Schwarz & Young.17 Woll, E., Hertig, A. T., Smith, G. V. S., and Johnson, L. C.: AM. J. 0~s~. & GYNEC. 56: 617, 1948. Kelly, Howard A.: Operative Gynecology, New York, 1898, D. Appleton & Company.
1. Meyer, 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.