Masculinizing tumor of the ovary of the adrenal type

MASCULINZZIHU

TUBBOR

OF TEE

OVARY

MARION DOUGLASS, M.D., F.A.C.S., (From

OF THE

AD3UWAL

TYPE

CLEVELAND, OHIO

the Department of Obstetrics and Gynecology, Western Reserve School of Medioine and the Lakeside Hospital)

University

HE phenomenon of sexual metamorphosis in adult life is always a dramatic Tstrationevent, and of striking interest to layman and scientist alike. The demonthat such Jekyll and Hyde mutations may be dependent upon a tumor no larger than a pea and are even reversible following ablation of the tumor, has a definite appeal to the imagination. The attention of clinical pathologists has been focused upon this group of tumors-the disgerminoma granulosa cell and arrhenoblastoma tumors which have excited widespread interest since Robert Meyer’s classical work was presented before the American Gynecological Society in 1931. To these may be added the Brenner tumor, theca-cell tumor, luteoma, and mesonephroma, OI adrenal tumor (masculinovoblastoma), some of which have been associated in some degree with these striking phenomena. Reis and Saphir have classified true masculinizing tumors as : 1. Arrhenoblastoma originating in male-directed sex cells persisting in the ovary from the early stages of gonadogenesis. 2. Disgerminoma arising from early gonadal cells before they acquired their power of specific sex direction. 3. Hypernephroma, interrenalism, or Gravitz tumor, adrenal rests or adenomas (Novak) misplaced within the ovary. 4. Luteomas with their disputed identity. Clinically, however, the full flower of masculinization seems to appear in the groups of arrhenoblastomas and adrenal tumors, and in Karsner’s dictum: “In spite of the lack of convincing evidence, it is probable that the beard, general hirsutism, male conformation, enlarged larynx, and clitoris are due to male sex hormone.” However, in repeated cases of undoubted masculinization the demonstration of excreted androgens in increased amounts has not been constant and, as stated by Novak, we probably do not understand many of the factors underlying sex differentiation. The factors involved in the relationship between the gonads and the adrenal cortex, close relatives embryologically, are not well known. Lesions in both the ovarian medulla and adrenal cortex produce masculiization in women which may be consonant with the Bauer hypothesis that adrenal tumors tend to masculinize the female and feminize the male, i.e., support the characters of the opposite sex. As proof of this perverse reaction, Schiller states he has seen two cases of adrenal-like testicular tumors associated with feminization in the male. The relationship of the dubious luteomas to this group of tumors, i.e., the adrenal-like tumor of the ovary, is still most obscure and confused, especially 190

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since progesterone itself may be androgenic. Novak is of the opinion that the luteoma, notoriously an evanescent structure, is doubtful as a source of this neoplastic growth, and it appears that most, if not all, the cases reported as masculinizing luteomas are probably of adrenal character in fmal analysis. He believes that the few ovarian adrenal tumors which have been observed, and also the adrenal ovarian “rests” reported by Saphir and Parker in 1936, have the structure of normal adrenal tissue, and are not of the type of the so-called hypernephroma of the ovary. There is great difficulty in distinguishing this tumor from the luteoma or thecoma, and this doubtful state is suggested in the name, masculinovoblastoma, of dubious derivation proposed for these tumors by Rottino. It is also difficult to decide whether to construe these tumors as adrenal rests or adrenal adenomas, assuming adenomas to be groups of morphologically normal, but functionally overactive cells ; and Novak mentions two cases with islands of typical adrenal cells near the ovarian hilum without masculinization. The mere presence of such cells thus is apparently not sufficient to cause masculinization. As far as luteomas are concerned, undoubtedly many of the reported cases have been of adrenal origin, and yet in the light of the apparent close chemical relationship between progesterone and testosterone, one must at least consider the possibility of masculinization occurring from the luteomas arising from the luteinization of granulosa-cell tumors. The weight of opinion, however, would seem to agree (Schiller) that most, if not all, of masculinizing luteomas are in reality of the adrenal type. Yet undisputed adrenal tumors in the ovary are very rare. The arguments pro and con, and the decisions reached on morphologic grounds purely, have reached a number of stalemates with Kermauner, Saphir, and others ranged against Novak, Meyer, and Schiller. The decision as to the identity of the tumors thus varying with the opinion of the most notable experts is obviously most unsatisfactory, yet hormonal studies systematically carried out as in the striking case (vide infra) have not done much to clarify the situation because the reported assays of estrogenie and adrogenic substances themselves and their ratios to each other have been fraught with conflicting evidence and contradictions. Differentiation on the basis of chemical content and ratios of cholesterol and fat content (phospholipids) and the presence or absence of reticulum (Traut and his associates) has been scarcely more fertile in establishing clearcut identification criteria. F’uchsinophil cells have been described as perhaps the underlying agency, but their definite significance is still shrouded in uncertainty. It seems obvious that only extremely careful reporting and study of this group of tumors, and the keenest analysis of them will develop a slide rule capable of giving us the answer in this nosologic confusion, with clinical manifestations, hormone assays, chemical consistency, and histologic appearance and their variational swings finally correlated. To this conflicting state of affairs we wish to add a case occurring in a woman following the menopause which showed marked changes of masculinization and following extirpation of the tumor, reversion to the bodily habitus

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of the normal postmenopausal woman. Appearance and disappearance of the stigmas of masculinization were paralleled by the gonadotropic hormone output as determined in the urine. Case Report The patient was a, white woman 48 years of age complaining of pain in the back and both lower quadrants which had developed seven years previously. After two months of treatment she had become better, then pain in both lower quadrants, vaginal discharge, and low backaches developed. These symptoms persisted and gradually became worse. During the previous two years the patient noticed a loss of much scalp hair, general hypertrichosis of chest, body, and legs, and a change in her facies. Her menses began at 17 years. Periods were regular, and varied between 42 and 49 days, lasting six to seven days with profuse bleeding. She had the menopause at 37 years of She was compelled to shave her face for age, with cessation of bleeding. cosmetic reasons daily, and her voice developed a bass tone. She experienced loss of libido for the past six years. Intercourse was also painful. She had three daughters, aged 25, 27, and 28 years and had no miscarriages. Operations : appendectomy twenty-two years ago. Physical examination : Temperature, 36.5” C. ; pulse, 98 ; blood pressure, 150/90. The patient was a well-developed, well-nourished, white woman, lying quietly in bed, and not appearing ill. Her facial features resembled those of a male. Chest: Large male type. Breasts : Small, soft, rather atrophic ; nipples flat; no masses. Abdomen was rotund and seemed to bulge at the flanks. No definite iluid wave could be made out, although the abdomen had a dull sound to percussion. Hair: There was a marked overgrowth of hair on the face, chest, abdomen, and lower extremities. Hair on the scalp was thin and there was an area of baldness. Hair over the temporal regions was short and masculine in distribution. Extremities : Normal development and function. Hands were not stubby and fingers were not thickened. Head and face: male appear&me. Voice was basso. No prognathism was present. Bridge of the nose and supraorbital regions were not unusually prominent. Urine on Jan. 20, 1942 was normal; blood was: white blood cells, 8,400; red blood cells, 6,350,OOO ; hemoglobin, 112 per cent. Blood on Jan. 21, 1942: white blood cells, 9,000 ; red blood cells, 6,000,OOO ; hemoglobin, 105 per cent. Basal metabolic rate on Jan. 21, 1942 was -8. Wassermann was negative. Blood sugar was 85 mg. per 100 C.C. X-ray of sella and pyelograms was negative. Operation : Perinorrhaphy, subtotal hysterectomy, bilateral salpingoophorectomy. Pelvic examination revealed the fundus to be large, smooth, and somewhat limited in mobility. The adnexa seemed enlarged, and a definite tumor was palpable on the right. On this basis, a preoperative diagnosis of masculinizing tumor of the right ovary, presumably arrhenoblastoma, was made. The uterus was found to be in the cul-de-sac. large in size, and deeply congested. There were, however, no myomas present. The engorgement of the uterus and the deep red color were rather striking ; the tubes also showed this congestion, otherwise they were normal. The left ovary was somewhat enlarged, free from adhesions. The right ovary was detinitelg hypertrophied, being approximately 4 cm. in its largest diameter; it was distinctly hard and presented somewhat rounded projections from its surface at a pole distant from the hilum. The ovaries were globular, light yellow in color, suggesting marked cellularity in consistency, but presenting no discrete tumor. The sur-

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faces of the ovaries were smooth, showing no trace of the atrophic pitting and There were no scarring of the surface of a typical postmenopausal atrophy. adhesions. Both kidneys were palpated and seemed to be normal in size and shape. The adrenals presented no abnormality at palpation. The gall bladder was negative for stones. Bilateral salpingoophorectomy and subtotal hysterectomy were performed. Pathologic Report.-Adrenal cortical tumor of the right ovary. No pathologic diagnosis of left ovary. Focal recent hemorrhage into tmyometrium, atrophy of endometrium, slight chronic bilateral salpingitis.

Fig. faeies.

Fig.

l.-Preoperative

Fig. %.-Appearance pearance of abnormal

1. appearance

one hirsutism.

of

patient.

year postoperative. Euphoria apparent

Typical Reappearance in patient’s

Fig. 2. hypertrichosis of feminine demeanor.

and

masculine

facies,

disap-

The left ovary weighed 5 Gm. and measured 2.7 by 2 by 1.5 cm., and the right ovary was not weighed, but it measured 3.2 by 2 by 0.9 cm. The right ovary had an external surface which was pinkish gray, corrugated, and in one region elevated. It was firm, sectioned with moderate resistance and the cut surface was slightly elevated. Near the center of the ovary there was a tumor mass which measured 1.4 by 1.2 by 0.8 cm. This tumor mass was light brown, firm, and fleshy, and its eut surface was uniformly brown, and on it there were multiple small red foci. The tumor was sharply demarcated from

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Am. J. Obst. & Gynec. February, 194 7

DOUGLASS

the surrounding tissue on one edge, and on the opposite it blended with the adjoining tissue, and in this region the adjoining tissue was mottled light brown and pale yellow. The adjoining tissue was pale yellow and surrounded by a pinkish gray capsule. The left ovary was pinkish yellow and had a corrugated external surface. It was firm, sectioned with moderate resistance, and the cut surface bulged slightly and was pinkish yellow. In one region the cut surface was somewhat sections were embedded. fieshy and was pale pinkish gray. Representative Sections of the left ovary showed the stroma to be abundant, compactly arranged, and richly cellular. There were numerous corpora albicantia, a,nd in the substance of the ovary there were many small medium sized arteries that showed intimal and medial thickening and hyalinization. There was also one small cyst that was lined with flattened epithelium, and contained some pale pink structureless material. The vessels in the surrounding connective tissue showed marked intimal proliferation with narrowing of the lumens.

3. baldness and regression for the age group. one year postoperative,

Fig.

Fig. Pig. 3.-Preoperative i.e., masculine stigmas Fig. 4.-Appearance ing hair on crown.

of hair showing

at the crown reappearance

4. and

over

of thick,

the closely

temples, grow-

Sections of the right ovary including a portion of the tumor were stained with hematoxylin and eosin, Sudan Black, Sudan IV, and Nile blue sulfate, Stains for Fuchsinophil granules were not made. Recent observations indicated that these were probably of no important signifioance in the diagnosis of androgenic tissue (Karsner) . In the sections there was considerable normal ovarian stroma which was richly cellular and compactly arranged. There was also an occasional corpus albioans, and there were many small arteries showing intimal and medial thickening and hyalinization. The tumor was not eaoapaulated, and was mod-

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erately cellular. The cells of the tumor were relatively large, and were for the most part cuboidal or polyhedral in outline. They had abundant pink, granular cytoplasma and relatively large cir lar or oval nuclei that were moderately chromatic. In many instances, t Y e cytoplasm of the cells was

shell

5. showing preoperative, Anger.) one year postoperative.

Fig.

Fig.

Fig. 5.-Perineum (Compare size, index Fig. B.-Perineum, perineal hirsutism.

Fig. 7. Fig. ‘I.-External surface of right ovary Fig. 8.-Median sagittal section of right of cortex is seen over the surface.

hypertrichosis Marked

diminution

and

6. hypertrophy

in size of clitoris.

Fig. 8. at operation. Approximately actual ovary, showing tumor, intrinsic in

of

clitoris. Normal

size. ovary.

A

relatively clear. The tumor cells had no distinctive architectural arrangement. They were present in irregular sheets and groups, and there was no acinus or tubule formation. In general, the cells simulated those ordinarily seen in adrenal cortex. There were a few cells with large deep chromatic nuclei, but in the sections examined there were no bizarre nuclear forms or abnormal

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9. .-Strands of ‘rn atfon. 1.O.-High-power

tubule% boundZi~

adrenal-like view

cells showing

Fig. 10. in irregular cells

resembling

Februasy,

arrangement adrenal

There cells

with

is no

acinue

well-d Mined

1947

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mitotic figures. In the sections prepared with special stains there were numerous very small droplets of lipoidal material in the cytoplasm’of many of the tumor cells. Since operation., the scalp hair is growing short and thick. The patient believes facial hair is diminishing in amount and rapidity of growth, and definite hairless areas are appearing on the abdomen and chest. The facies shows smoothing out of wrinkles. The clitoris shows definite involution. Follow-up of this patient over a period of two years has shown complete restitution of normal feminine facies and habitus, with scalp hair normally profuse and covering the entire crown. Facial hair, however, has been more stubborn in its persistence, and still requires shaving every third or fourth day.’ This, however, is not incompatible with the well-known postmenopausal tendency to general hirsutism, and generally an increase in facial hirsutism, only too often so noticeable, particularly in brunette women in the form of the feminine mustache. Body hair has completely disappeared, except for the normal feminine distribution in the normal pubic area. The anterior surface of the thighs are clear of excessive growth. The clitoris is normal in size and appearance. Pelvic examination revealed no trace of tumor. Hormone assays were performed with the following results : The excretion of 17-ketosteroids in the urine before operation was 11.6 mg. in twenty-four hours, and the androgen excretion as determined by bioassay was 33 international units. These values are within the normal range for adult females, and they are in contrast to the high values which are found in cases of masculipizing tumors which arise within the adrenal cortex. A number of assays made within the first week after operation yielded values ranging from 3.4 to 6.5 mg. Such a fall could be due to the stress imposed by the operative procedure itself, and it need not necessarily be interpreted as being due to the removal of the tumor. Two months after the operation the excretion has risen to 8.5 mg. per twenty-four hours. The urinary gonadotropic hormone output before operation was less than 4 mouse uterine units per day. This low value is of considerable interest when contrasted with a high level of 64 units obtained two months postoperatively. The latter high value is normal after the menopause, and the previous low excretion would be expected if there had been secretion of an active sex hormone by the tumor. The preoperative excretion of estrogen was not high (less than 75 international units in twenty-four hours), and no nregnandiol was detected. A high urinary output of 1’7-ketosteroids points rather definitely to adrenal origin of the tumor on the basis of previously reported cases. In the case reported here, on the basis of undeniable signs of masculinization and their regression following removal of the tumor, it seems permissible to assume that the preoperative level of 11.6 mg., though within the high limits of normal, represented a comparatively high level for this particular patient. The subsequent fluctuations post-operatively, varied between 3.4 and 8.5 mg. per twenty-four hours. This, in the light of the behavior of gonadotropic hormone, is of interest. Gonadotropic hormone varied between 4 Mu and 64, the postoperative level. This suggests a more or less typical castration reaction. In the light of the difficulty of identification of these tumors on the basis of lipoidal content or morphology, fluctuations in hormone output are all the more important in identification of these tumors.

There are a number of features in this case that seem noteworthy, viz., although the patient gave a history of menopause at 37 years with rather

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Am. f. Obst. &&a. Febrwry, 1947

severe symptoms, the ovaries were both enlarged to two or three times normai size and lacked the typical atrophic wrinkled and pitted appearance of the senile ovary, and were smooth and cellular-looking. The uterus was enlarged and engorged in appearance, not at all the small atrophic fibrous senile uterus of a woman ten years post menopause. This patient showed the characteristic tendency toward hypertension fairly frequent in the reported cases. The blood sugar was normal. Polycythemia was present. General appearance of the tumor suggests definite adrenal cortical cells with well-marked cell boundaries. In spite of functional behavior of the tumor in terms of 17-ketosteroids and bioassay in international units, its demonstrable output of androgens is extremely low in comparison with other reported cases, suggesting either that androgens in large amounts are not necessary to produce masculinization, or that our means of measuring them quantitatively are as yet not sufficiently refined as to be entirely reliable. There were definite masculine stigmas of approximately two years’ duration, with masculine type of baldness and recession of hair at temporal regions, rugged deeply lined faeies with marked hypertrichosis of chest, abdomen, and legs, definite marked hypertrophy of the clitoris and masculine type pubic hair distribution. Complete recession of signs of masculinization and resumption of feminine habitus followed ablation of the tumor. Acknowledgment is made to Dr. H. T. Karsner for the pathologic Drs. R. A. Shipley and R. I. Dorfman for the hormonal assays.

report,

and to

References Bang, F.: Acta path. et microbial. Scandinav., Suppl. 38, p. 91, 1938. Broster, L. R., and Vines, H. W. C.: The Adrenal Cortex: A Surgical and Pathological Study, London, 1933, H. K. Lewis & Co., Ltd. Geist, 5. H.: Aaa. J.OBST.& GPNEC.~~: 650,1935. Greene, H., and Lapp, W.: AM.J.OBST.& GYNEC. 47: 63,1944. Karsner, H. T.: Certain Ovarian Tumors Associated With Sexual Endocrine Dyefunctian, Thomas Dent Mutter Lecture II, The College of Physicians of Philadelphia, December 6, 1939. IG&ele lf, et al.: Aar.J. OBST.&GPNEC.~~: 43,1944. - AM. J. OBST.& GYNEC. 36: 840,193s. Rottinb, i., and McGrath, J. F.: Arch. Int. Med. 63: 686,1939. Saphir, W., and Parker, M. L.: J. A.M. A. 107: 1286, 1936. Sehiller, W.: J. Obst. & Gynaec. Brit. Emp. 43: 1135, 1936. Schiller, W.: Discussion of paper by Rottino and MeGrath, V.S.