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Masculinovoblastoma: An adrenal cortical type of tumor of the ovary
MASCULINOVOBLASTOMA
: TUMOR
R. N. CAGAN, M.D., (From
the Department
AND
AN ADRENAL COETICAL OF THE OVABY
TYPE
HERBERT M. WOLFF, M.D., TRENTON,
of Medicine St.
and the Department Francis
of Obstetrics
and
OF
N. J. Gynecology,
Hospital)
ECRETING tumors of the ovary have the remarkable “Jekyll-Hyde” S ability to accentuate female traits by their production of estrogen-like steroids or to induce masculine features through their production of androgenlike compounds. The latter group of functioning tumors which cause masculinization include the arrhenoblastoma, dysgerminoma, hilum-cell tumor, was and the rare masculinovoblastoma. The term “masculinovoblastoma” introduced by Rottinol in 1939 to apply to those masculinizing ovarian tumors which microscopically resemble the adrenal cortex. Twenty-nine verified cases of masculinovoblastoma have been reported. Iverson* reviewed 15 cases in 1947. Merivale3 culled 9 more from the literature and added one of his own in 1951. Pati14 reported 2 and Michaelson and Rhoad@ each reported a case. We shall report the following case of a masculinovoblastoma for which urinary 17-ketosteroids and “pregnanediol complex”* were determined. Only a few of the more recent reports record the 24 hour urinary 17ketosteroid excretion, and Merivale’s report is the only case accompanied by “pregnanediol complex” excretion values. Case Presentation Mrs. T. M., a 29-year-old woman, born in Italy, complained of progressively developing hirsutism of one year’s duration, hoarseness of six months, and decrease in the size of the breasts and amenorrhea of three months’ duration. There was no changein sexual potentia. The patient had been married for 9 years, had been pregnant once, and had a 5-year-old son at the time of examination. She had been examined by one of us (FL M. W.) seven months prior to the present complaints and found to be normal. Previous history disclosed no other contributing facts. Photographs of the women in the patient’s immediate family showed no abnormal hirsutism. Examination disclosed a well-proportioned, attractive young woman with a hoarse The hair distribution showed a male voice. There was mild acne of the face and back. type of escutcheon, fuzz on the upper lip and chin, and a more moderate hair development on the lower abdomen and thighs. The blood pressure was 130/60. The thyroid was not The clitoris was of normal size. palpable. The breasts were small but well formed. *The analysis nique of Sommerville’ analysis determines
for “pregnanediol
was performed in accordance pregnanediol and pregnanetriol.6 complex” is used.
complex” which actually measures both, the term “pregnanediol s‘s5
with
the techBecause the
886
CAGAN
AND
WOLFF
Am. J. Obst. & Gynec. April,
1957
No abnormality was demonstrated in roentgenograms of the pituitary fossa, and in the intravenous pyelogram and presacral air insufflation to outline the suprarenal areas.* The blood count and hematocrit, glucose tolerance test, serum sodium, potassium, and carbon-dioxide combining power were within normal limits. After a 24 hour urine specimen was analyzed for 17-ketosteroids, cortisone was administered intramuscularly, 400 mg. per day, for four days. On the fourth day urine was obtained for li-ketosteroid tletermination. The 24 hour excretion of urinary steroidst is given in Table I. Before further steroid studies could be performed and because of clinical urgency, the patient was operated upon. TABLE
I.
TWENTY-FOUR-HOUR
EXCRETION
URINARY
OF STEFKUDS
NORMAL
17.Ketosteroid
121 mg.
63 mg.
12 mg.
8 mg.
5-17
46 mg.
‘ ‘ Pregnanediol complex ’ ’
1 mg. (early phase of cycle)
Fig.
I.-Right
ovarian
VALUES
mg. 15 mg. late phase of cycle)
tumor.
Through a lower left vertical rectus incision, extending from below the umbilicus to just above the symphysis pubis, the lower abdominal cavity was opened under genAbout $$ pint of straw-colored fluid was found in the pelvis. A right eral anesthesia. salpingo-oophorectomy, wedge biopsy of the left ovary, and appendectomy were performed. The right ovary was replaced by a yellowish-white, irregularly shaped tumor, which was freely movable and about the size of a tennis ball, resting on the right side of the posWhen the tumor was incised, following its removal, a broad, scalloped, terior pelvic wall. presacral
*Dr. tThe
of Jefferson
Benjamin Salway, insufflation. hormone analyses
air
Medical
College.
Department were
carried
of Surgery
of
out in the Division
St. Francis of Endocrine
Hospital, and
performed Cancer
the
Research
Volume 73 Number 4
MASCtJLINOVOBLASTOMA
887
bright-yellow area about lys cm. in width was seen at least 2% cm. beneath its caps& (Fig. 1). The tumor, at the periphery of the scalloped yellow area, was soft, which fact may have accounted for the lack of preoperative pelvic findings. On repeated section, the cut surfaces showed a circular scalloped band of orange-colored tissue which gross]? resembled adrenal gland. The microscopic examination* (Fig. 2) showed a section of ovarian tumor. Its out,er wall contained some compressed ovarian tissue recognized by ovarian stroma and the presence of a small follicle lined by typical follicular cells. There was mild edema of the stroma as well as compression. The center of the lesion was separated from the normal ovarian stroma by very loose fibrous tissue within which were observed thick-walled blood vessels and a considerable amount of frank blood. The tumor itself was composed of large sheets of cells. These appeared to have a very pale, slightly vacuolated cytoplasm and contined small amounts of granular material. The nuclei in most instances were centrally placed and appeared very small and pyknotic. The cell outlines were veq distinct and easy to discern. They appeared in many respects to be mirror images of those seen in normal adrenal tissue. No evidence of malignancy was noted within the tissue. The pathological diagnosis was masculinovoblastoma of the right ovary.
Fig,
?.---Microscopic
enlargement
of tumor
cells.
(X400;
reduced
1/4.)
Eight months later, the patient was examined and found to have a marked in hirsutism, enlargement of the breasts to normal size, and decrease in extent Her periods had become regular but the hoarseness persisted unchanged. ketosteroid excretion was 8 mg. per 24 hours.
diminution of the acne. The 17.
Comment At present, unless one can palpate a pelvic mass or visualize an adrenal tumor by air studies, there is no means by which the examiner can predict before operation whether a particular case of masculinization is due to an abnormality of the ovary or of the adrenal cortex. No combination of signs and symptoms can be used to designate either the ovary or the adrenal as the site of the masculinizing tumor.g The practical importance of knowing the *We pathological
are
grateful material
to Dr. included.
Solomon
Weintraub.
Pathologist,
St. Francis
Hospital, for the
888
CAGAN
AND
WOLFF
Am. J. Obst. k Gynec. April. 1957
location of the trouble preoperatively is evident. Therefore it is important to document cases of masculinovoblastoma, not only because of their rarity of the ovary, but also because additional and interest as “adrenal tumors” observations in these cases may make future recognition simpler. With added knowledge, the uncertainty of the site of the tumor at laparotomy and the occasional need for multiple surgical procedures may be eliminated. In addition, further light may be shed on the problem of hirsutism in general. Presented with a case of masculinization, several diagnostic avenues must be explored. Is the symptom complex simply a constitutional defect? Can the pituitary be absolved of responsibility? If the adrenal cortex is responsible, is it hyperplasia or tumor, malignant or benign, left or right adrenal? Or is the ovary at fault? The decision in a particular case that a pathological masculinizing syndrome may exist is the first and sometimes the most difficult step. This is so because, once such a conclusion is reached, the physician must spend time, effort, and the patient’s money looking for the aberration. The justifiable reluctance of most physicians to investigate such a case is evident if one notes the delay from onset of symptoms to treatment in these instances. A review of the literature showed that most patients suffered three to five years without treatment, and one patient suffered from a secreting tumor for 32 years until it was investigated.3 Pituitary hypersecretion usually does not cause pure masculinization or defeminization as seen in this instance. However, a hypersecretory adrenal cortex could produce such a picture. The observed normal urogram and perirenal x-rays combined with an increase in excretion of 17-ketosteroids (121 mg.) and of “pregnanediol complex” (46 mg.) suggested adrenal cortical hyperplasia. However, in adrenal hyperplasia, ideally, one would expect an elevated 17-ketosteroid, which is depressed to normal values during cortisone administration, and an increased excretion of ‘ ‘pregnanediol complex. “* Actually, neither the pituitary nor adrenal was at fault in this instance, for the patient had an “adrenal-cortical type” of secreting tumor of the ovary, a masculinovoblastoma. Although there are exceptions, Kepler9 felt that an increased 17-ketosteroid excretion is typical of this tumor. Merivalea found an increased “pregnanediol complex” excretion as we did. Since the period of cortisone administration in this case was so short and since the results of 17-ketosteroid excretion during this period were not clear-cut, we feel that no conclusion is warranted from the scant data. The decrease in 24 hour urinary excretion from 121 mg. to 63 mg. of 17-ketosteroid could be a biological variation in day-to-day excretion of the steroid rather than the result of cortisone suppression of the adrenal cortex. The excessive production in the urine of pregnanediol and especially pregnanetriol has been considered to be characteristic of cases of adrenal cortical hyperplasia with virilism.* This finding has led to the belief that the basic defect in this disease is a relative inability of the adrenal to hydroxylate a C-21 steroid at the lip and 21 positions. *O As a resnlt of this aberration
Volume Number
MASCULINOVOBLASTOMA
73 4
#I,
larger quantities of a virilizing, l1 but incomplete adrenal steroid, probably 17-hydroxyprogesterone, are produced. This substance is thought to be an intermediary in the synthesis of compound 1;‘ in the adrenal gland.12 However, this compound fails to inhibit the pituitary ACTH production to an adequate extent and thus permits the continuing production of ACTH with the resultant adrenal hyperplasia.1° The hyperplastic adrenal cortex eventually produces enough of the physiologic pituitary inhibitor, l’l-hydroxycorticosterone or compound F, to bring the production of ACTH to a steady, although excessive, state. In the interim, abnormally large quantities of 17-ketosteroid, the probable metabolic end product of the aforementioned l7-hydroxyprogesterone, are excreted in the urine.lO In this case of a masculinovoblastoma, the excessive urinary steroid excretion, 17-ketosteroid and “pregnanediol complex,” coupled with t,he clinical syndrome and microscopic pathology, recalls cases of virilism due to adrenal cortical hyperplasia. Whether the pathological physiology is the same as in adrenal hyperplasia cannot be answered at this time. However, the similarity in clinical picture and in urinary steroid excretion is striking and reinforces the concept, previously suggested, that the two have a common cellular origin.13 Nevertheless, the problem of differentiating the two still remains. It is unfortunate in the present case that more urinary steroid analyses could not have been completed during t,he period of cortisone ntlministration and before operation.
Conclusions A case of a masculinovoblastoma The values for 17-ketosteroid the urine have been recorded.
has been presented. and “pregnanediol complex”
excretion
in
Furthermore, the increasing evidence indicting the masculinovoblastoma as an adrenal-cortical type of tumor in the ovary has been cited.
References ii* 3: 4. 5. 6. 7. ::
Rottino, A., and McGrath, J. F.: Arch. Int. Med. 63: 686, 1939. Iverson, L.: Burg., Gynec. & Obst. 84: 213,1947. Merivale, W. H., and Forman, L.: Brit. M. J. 1: 560, 1951. Patil. H. B.: Indian M. Gaz. 86: 154.1951. Michielson, E. T.: New York State’J. Med. 50: 1745, 1950. Rhoads, J. E., Zintel, H. A., and Horn, R. E., Jr.: J. A. M. A. 148: 551,1952. Sommerville, I. F., and Marrian, G. F.: Lancet 2: 89, 1948. Bongiovanni, A. M. : Bull. Johns Hopkins Hosp. 92: 244, 1953. Kepler, E. J., Dockerty, M. B., and Priestly, J. T.: AM. J. OBST. & GYNEC.
10. Jailer,
1944.
47: 43,
J. W.: Bull. New York Acad. Med. 29: 377,1953. 11. PAffner, J. J., and North, H. B.: J. Biol. Chem. 139: 855, 1941. O., Zaffaroni, A., Jacobsen, R., Levy, H., Jeanloz, R., Schenker, V., and 12. Hechter, Pincus, G. : In Pincus, G., editor: Recent Progress in Hormone Research, New York, 1951, Academic Press, Inc., vol. 6, pp. 215-241. 13. Green, H. J., and Lapp, W. A.: AM. J. OBST. & GYNEC. 47: 63, 1944.
: TUMOR
R. N. CAGAN, M.D., (From
the Department
AND
AN ADRENAL COETICAL OF THE OVABY
TYPE
HERBERT M. WOLFF, M.D., TRENTON,
of Medicine St.
and the Department Francis
of Obstetrics
and
OF
N. J. Gynecology,
Hospital)
ECRETING tumors of the ovary have the remarkable “Jekyll-Hyde” S ability to accentuate female traits by their production of estrogen-like steroids or to induce masculine features through their production of androgenlike compounds. The latter group of functioning tumors which cause masculinization include the arrhenoblastoma, dysgerminoma, hilum-cell tumor, was and the rare masculinovoblastoma. The term “masculinovoblastoma” introduced by Rottinol in 1939 to apply to those masculinizing ovarian tumors which microscopically resemble the adrenal cortex. Twenty-nine verified cases of masculinovoblastoma have been reported. Iverson* reviewed 15 cases in 1947. Merivale3 culled 9 more from the literature and added one of his own in 1951. Pati14 reported 2 and Michaelson and Rhoad@ each reported a case. We shall report the following case of a masculinovoblastoma for which urinary 17-ketosteroids and “pregnanediol complex”* were determined. Only a few of the more recent reports record the 24 hour urinary 17ketosteroid excretion, and Merivale’s report is the only case accompanied by “pregnanediol complex” excretion values. Case Presentation Mrs. T. M., a 29-year-old woman, born in Italy, complained of progressively developing hirsutism of one year’s duration, hoarseness of six months, and decrease in the size of the breasts and amenorrhea of three months’ duration. There was no changein sexual potentia. The patient had been married for 9 years, had been pregnant once, and had a 5-year-old son at the time of examination. She had been examined by one of us (FL M. W.) seven months prior to the present complaints and found to be normal. Previous history disclosed no other contributing facts. Photographs of the women in the patient’s immediate family showed no abnormal hirsutism. Examination disclosed a well-proportioned, attractive young woman with a hoarse The hair distribution showed a male voice. There was mild acne of the face and back. type of escutcheon, fuzz on the upper lip and chin, and a more moderate hair development on the lower abdomen and thighs. The blood pressure was 130/60. The thyroid was not The clitoris was of normal size. palpable. The breasts were small but well formed. *The analysis nique of Sommerville’ analysis determines
for “pregnanediol
was performed in accordance pregnanediol and pregnanetriol.6 complex” is used.
complex” which actually measures both, the term “pregnanediol s‘s5
with
the techBecause the
886
CAGAN
AND
WOLFF
Am. J. Obst. & Gynec. April,
1957
No abnormality was demonstrated in roentgenograms of the pituitary fossa, and in the intravenous pyelogram and presacral air insufflation to outline the suprarenal areas.* The blood count and hematocrit, glucose tolerance test, serum sodium, potassium, and carbon-dioxide combining power were within normal limits. After a 24 hour urine specimen was analyzed for 17-ketosteroids, cortisone was administered intramuscularly, 400 mg. per day, for four days. On the fourth day urine was obtained for li-ketosteroid tletermination. The 24 hour excretion of urinary steroidst is given in Table I. Before further steroid studies could be performed and because of clinical urgency, the patient was operated upon. TABLE
I.
TWENTY-FOUR-HOUR
EXCRETION
URINARY
OF STEFKUDS
NORMAL
17.Ketosteroid
121 mg.
63 mg.
12 mg.
8 mg.
5-17
46 mg.
‘ ‘ Pregnanediol complex ’ ’
1 mg. (early phase of cycle)
Fig.
I.-Right
ovarian
VALUES
mg. 15 mg. late phase of cycle)
tumor.
Through a lower left vertical rectus incision, extending from below the umbilicus to just above the symphysis pubis, the lower abdominal cavity was opened under genAbout $$ pint of straw-colored fluid was found in the pelvis. A right eral anesthesia. salpingo-oophorectomy, wedge biopsy of the left ovary, and appendectomy were performed. The right ovary was replaced by a yellowish-white, irregularly shaped tumor, which was freely movable and about the size of a tennis ball, resting on the right side of the posWhen the tumor was incised, following its removal, a broad, scalloped, terior pelvic wall. presacral
*Dr. tThe
of Jefferson
Benjamin Salway, insufflation. hormone analyses
air
Medical
College.
Department were
carried
of Surgery
of
out in the Division
St. Francis of Endocrine
Hospital, and
performed Cancer
the
Research
Volume 73 Number 4
MASCtJLINOVOBLASTOMA
887
bright-yellow area about lys cm. in width was seen at least 2% cm. beneath its caps& (Fig. 1). The tumor, at the periphery of the scalloped yellow area, was soft, which fact may have accounted for the lack of preoperative pelvic findings. On repeated section, the cut surfaces showed a circular scalloped band of orange-colored tissue which gross]? resembled adrenal gland. The microscopic examination* (Fig. 2) showed a section of ovarian tumor. Its out,er wall contained some compressed ovarian tissue recognized by ovarian stroma and the presence of a small follicle lined by typical follicular cells. There was mild edema of the stroma as well as compression. The center of the lesion was separated from the normal ovarian stroma by very loose fibrous tissue within which were observed thick-walled blood vessels and a considerable amount of frank blood. The tumor itself was composed of large sheets of cells. These appeared to have a very pale, slightly vacuolated cytoplasm and contined small amounts of granular material. The nuclei in most instances were centrally placed and appeared very small and pyknotic. The cell outlines were veq distinct and easy to discern. They appeared in many respects to be mirror images of those seen in normal adrenal tissue. No evidence of malignancy was noted within the tissue. The pathological diagnosis was masculinovoblastoma of the right ovary.
Fig,
?.---Microscopic
enlargement
of tumor
cells.
(X400;
reduced
1/4.)
Eight months later, the patient was examined and found to have a marked in hirsutism, enlargement of the breasts to normal size, and decrease in extent Her periods had become regular but the hoarseness persisted unchanged. ketosteroid excretion was 8 mg. per 24 hours.
diminution of the acne. The 17.
Comment At present, unless one can palpate a pelvic mass or visualize an adrenal tumor by air studies, there is no means by which the examiner can predict before operation whether a particular case of masculinization is due to an abnormality of the ovary or of the adrenal cortex. No combination of signs and symptoms can be used to designate either the ovary or the adrenal as the site of the masculinizing tumor.g The practical importance of knowing the *We pathological
are
grateful material
to Dr. included.
Solomon
Weintraub.
Pathologist,
St. Francis
Hospital, for the
888
CAGAN
AND
WOLFF
Am. J. Obst. k Gynec. April. 1957
location of the trouble preoperatively is evident. Therefore it is important to document cases of masculinovoblastoma, not only because of their rarity of the ovary, but also because additional and interest as “adrenal tumors” observations in these cases may make future recognition simpler. With added knowledge, the uncertainty of the site of the tumor at laparotomy and the occasional need for multiple surgical procedures may be eliminated. In addition, further light may be shed on the problem of hirsutism in general. Presented with a case of masculinization, several diagnostic avenues must be explored. Is the symptom complex simply a constitutional defect? Can the pituitary be absolved of responsibility? If the adrenal cortex is responsible, is it hyperplasia or tumor, malignant or benign, left or right adrenal? Or is the ovary at fault? The decision in a particular case that a pathological masculinizing syndrome may exist is the first and sometimes the most difficult step. This is so because, once such a conclusion is reached, the physician must spend time, effort, and the patient’s money looking for the aberration. The justifiable reluctance of most physicians to investigate such a case is evident if one notes the delay from onset of symptoms to treatment in these instances. A review of the literature showed that most patients suffered three to five years without treatment, and one patient suffered from a secreting tumor for 32 years until it was investigated.3 Pituitary hypersecretion usually does not cause pure masculinization or defeminization as seen in this instance. However, a hypersecretory adrenal cortex could produce such a picture. The observed normal urogram and perirenal x-rays combined with an increase in excretion of 17-ketosteroids (121 mg.) and of “pregnanediol complex” (46 mg.) suggested adrenal cortical hyperplasia. However, in adrenal hyperplasia, ideally, one would expect an elevated 17-ketosteroid, which is depressed to normal values during cortisone administration, and an increased excretion of ‘ ‘pregnanediol complex. “* Actually, neither the pituitary nor adrenal was at fault in this instance, for the patient had an “adrenal-cortical type” of secreting tumor of the ovary, a masculinovoblastoma. Although there are exceptions, Kepler9 felt that an increased 17-ketosteroid excretion is typical of this tumor. Merivalea found an increased “pregnanediol complex” excretion as we did. Since the period of cortisone administration in this case was so short and since the results of 17-ketosteroid excretion during this period were not clear-cut, we feel that no conclusion is warranted from the scant data. The decrease in 24 hour urinary excretion from 121 mg. to 63 mg. of 17-ketosteroid could be a biological variation in day-to-day excretion of the steroid rather than the result of cortisone suppression of the adrenal cortex. The excessive production in the urine of pregnanediol and especially pregnanetriol has been considered to be characteristic of cases of adrenal cortical hyperplasia with virilism.* This finding has led to the belief that the basic defect in this disease is a relative inability of the adrenal to hydroxylate a C-21 steroid at the lip and 21 positions. *O As a resnlt of this aberration
Volume Number
MASCULINOVOBLASTOMA
73 4
#I,
larger quantities of a virilizing, l1 but incomplete adrenal steroid, probably 17-hydroxyprogesterone, are produced. This substance is thought to be an intermediary in the synthesis of compound 1;‘ in the adrenal gland.12 However, this compound fails to inhibit the pituitary ACTH production to an adequate extent and thus permits the continuing production of ACTH with the resultant adrenal hyperplasia.1° The hyperplastic adrenal cortex eventually produces enough of the physiologic pituitary inhibitor, l’l-hydroxycorticosterone or compound F, to bring the production of ACTH to a steady, although excessive, state. In the interim, abnormally large quantities of 17-ketosteroid, the probable metabolic end product of the aforementioned l7-hydroxyprogesterone, are excreted in the urine.lO In this case of a masculinovoblastoma, the excessive urinary steroid excretion, 17-ketosteroid and “pregnanediol complex,” coupled with t,he clinical syndrome and microscopic pathology, recalls cases of virilism due to adrenal cortical hyperplasia. Whether the pathological physiology is the same as in adrenal hyperplasia cannot be answered at this time. However, the similarity in clinical picture and in urinary steroid excretion is striking and reinforces the concept, previously suggested, that the two have a common cellular origin.13 Nevertheless, the problem of differentiating the two still remains. It is unfortunate in the present case that more urinary steroid analyses could not have been completed during t,he period of cortisone ntlministration and before operation.
Conclusions A case of a masculinovoblastoma The values for 17-ketosteroid the urine have been recorded.
has been presented. and “pregnanediol complex”
excretion
in
Furthermore, the increasing evidence indicting the masculinovoblastoma as an adrenal-cortical type of tumor in the ovary has been cited.
References ii* 3: 4. 5. 6. 7. ::
Rottino, A., and McGrath, J. F.: Arch. Int. Med. 63: 686, 1939. Iverson, L.: Burg., Gynec. & Obst. 84: 213,1947. Merivale, W. H., and Forman, L.: Brit. M. J. 1: 560, 1951. Patil. H. B.: Indian M. Gaz. 86: 154.1951. Michielson, E. T.: New York State’J. Med. 50: 1745, 1950. Rhoads, J. E., Zintel, H. A., and Horn, R. E., Jr.: J. A. M. A. 148: 551,1952. Sommerville, I. F., and Marrian, G. F.: Lancet 2: 89, 1948. Bongiovanni, A. M. : Bull. Johns Hopkins Hosp. 92: 244, 1953. Kepler, E. J., Dockerty, M. B., and Priestly, J. T.: AM. J. OBST. & GYNEC.
10. Jailer,
1944.
47: 43,
J. W.: Bull. New York Acad. Med. 29: 377,1953. 11. PAffner, J. J., and North, H. B.: J. Biol. Chem. 139: 855, 1941. O., Zaffaroni, A., Jacobsen, R., Levy, H., Jeanloz, R., Schenker, V., and 12. Hechter, Pincus, G. : In Pincus, G., editor: Recent Progress in Hormone Research, New York, 1951, Academic Press, Inc., vol. 6, pp. 215-241. 13. Green, H. J., and Lapp, W. A.: AM. J. OBST. & GYNEC. 47: 63, 1944.