FEMINIZING ADRENOCORTICAL CARCINOMA IN A MAN
J. L. GABRILOVE, MD,* G. L. NICOLIS, MD,+ R. U. HAUSKNECHT, MD, AND H. H. WOTIZ, PHD **
A second instance of a feminizing adrenocortical tumor studied in this lab- oratory is reported. A marked increase in the production rates of estrone and estradiol was demonstrated as well as in the urinary excretion of estogens. These latter were partitioned into 16-hydroxyestrone, 16-ketoestradiol, and 16-epiestriol as well as the classical estrogens. The secretory rate of cortisol was low whereas that of 11-deoxycortisol was markedly increased. The urinary excretion of testosterone was normal in spite of marked feminization and atrophy of the testes. Of interest was the demonstration of the marked con- version into estrogen of androstenedione and testosterone administered in- travenously. In addition, 8 further instances of feminizing adrenocortical carcinoma collected from the literature are reviewed.
R ECENTLY WE REVIEWED THE CLINICAL, pathologic, and biochemical features of 52 men with feminizing adrenocortical tu- mors.10 In the present study, we report a sec- ond such patient investigated in this labora- tory. In this subject, estrogen production rates, the urinary excretion of estrogen and of testosterone, and the conversion of intraven- ously administered androstenedione and test- osterone into estrogen are detailed together with more conventional observations. In ad- dition, 8 other instances of the syndrome not included in the previous report are reviewed.
MATERIALS AND METHODS
The urinary excretion of the neutral 17- ketosteroids was measured by the method of Drekter et al.6 and of the 17-hydroxycor-
From the Endocrine Research Laboratory of the De- partment of Medicine and the Department of Obstet- rics and Gynecology, The Mount Sinai Hospital and Mount Sinai School of Medicine, New York, N.Y., and the Department of Biochemistry, Boston University, School of Medicine, Boston, Mass.
Aided by grants HD 02764 and FR-71 from the Na- tional Institutes of Health.
* Clinical Professor of Medicine, Mount Sinai School of Medicine; t Assistant Professor of Medicine, Mount Sinai School of Medicine. Special Fellow of the NIH; # Assistant Professor of Obstetrics and Gynecology, Mount Sinai School of Medicine; ** Professor of Bio- chemistry, Boston University School of Medicine.
The authors are indebted to Dr. Benjamin Krentz for referring this patient for study; to Mrs. Asya Kadis for translation of reference 12 from Russian, and to Dr. Y. Suzuki for translation of references 13 and 14 from Japanese.
Received for publication July 21, 1969.
ticoids by the Peterson23 modification of the method of Silber and Porter.28 Urinary estro- gens were assayed by gas chromatography.33 Estrogen production rates were measured ac- cording to the procedure of Siiteri and Mac- Donald.27 The secretory rates of cortisol and 11-deoxycortisol were determined as previ- ously described.11 Urinary testosterone was measured by a modification of the method of Futterweit et al.8,11 Tracer doses of androstene- dione-3H and testosterone-3H were injected intravenously on separate occasions. The urine was collected for 3 days and the percent distribution of radioactivity in the estrone and estriol fractions was measured after puri- fication to constant specific activity. Conver- sions of the radioactive androgens into estrone and estriol were calculated by correcting these results for the recovery of radioactivity ob- tained after the intravenous injection of estrone-14C and estradiol-3H during the pro- duction rate studies. This indirect correction was necessary because carbon-14-labelled estro- gens were unfortunately not given concomi- tantly with the tritium-labelled androgens.
CASE REPORT
A 55-year-old Negro man was first ad- mitted to The Mount Sinai Hospital on Aug. 6, 1967, because of gynecomastia and a left upper quadrant mass. He stated that al- though he had noted the onset of secondary sexual characteristics with pubic hair at the age of 17 years and axillary hair at 20 years of
age he had not shaved till the age of 35 years. He had had normal libido and potentia until 5 to 10 years prior to admission, and he claimed to have fathered 3 children. Five years prior to entering the hospital he had weighed 195 1b., was quite muscular, and worked as a steel cutter. At that time, he was found to be hypertensive. Because of this and a question of an aortic aneurysm, he was given a medical discharge from his employ- ment.
About 11/2 to 2 years prior to admission, he noted anorexia, weakness, and weight loss. About the same time, he experienced painless hematuria and, subsequently, enlargement of the breasts. The breasts became full and firm, but no secretion was observed. In the past year he had noted an “annoyance” in the left upper quadrant, dyspnea on exertion, and some periareolar pigmentation. He had lost 35 to 40 1b. over the past 2 years.
He was admitted to another hospital where, because of his appearance, he was thought possibly to have Marfan’s syndrome. He was found’ to have minimal hyperten- sion and, on roentgenography, an uncoiled aorta. The breasts were enlarged. A large, firm, nontender, fixed left upper quadrant mass was palpable. The testes were soft and atrophic. On x-ray examination, “coin” le- sions were noted in both lungs, and a large calcium-containing mass was present above the left kidney. He was transferred to The Mount Sinai Hospital for further investigation.
On physical examination at The Mount Sinai Hospital, it was noted that he was tall and lean with long tapering fingers. The palate was high and arched. The blood pres- sure was 140/80 mm Hg. A bilateral arcus senilis was present. There was no dislocation of the lens. Marked bilateral gynecomastia was present, and there was periareolar pig- mentation. The heart was not enlarged. No thrills nor murmurs were present. The lungs were clear to ausculation and percussion. In the left upper quadrant, a large, firm, hard mass was present. The liver edge was palpa- ble 6 finger breadths below the costal margin. The testes were atrophic and soft. No edema was present. A varicocele was present on the left (Fig. 1).
The laboratory examination revealed the urine to have a specific gravity of 1.010, pH 5.5, no protein, no glucose, and a negative microscopic examination. The blood hemo- globin was 11.2 g/100 ml, the hematocrit 35%, the white blood cell count was 10,400/ mm3 with 75% segmented polymorphonu- clear leukocytes, 3% band forms, 1% eosino- philic leucocytes, 16% lymphocytes, and 5% monocytes. The blood Wasserman reaction
was negative. The blood urea nitrogen was 17 mg/100 ml and sugar 80 mg/100 ml. The serum sodium was 140/meq/L, potassium 4.8 meq/L, chloride 100 meq/L, carbon dioxide content 27 meq/L, total protein 7.3 g/100 ml, bilirubin 0.4 mg/100 ml, cholesterol 192 mg/ 100 ml, alkaline phosphatase 11 King-Arm- strong units/100 ml, serum glutamic oxala- cetic transaminase 55 units/ml/min, uric acid 3.3 mg/100 ml, and creatinine 0.9 mg/100 ml. The glucose tolerance test gave the fol- lowing values (mg/100 ml): fasting 86; 1/2 hour 128; 1 hour 122; 2 hours 101; 3 hours 66. The sedimentation rate was 93 mm/1 hour. The electrocardiogram revealed non- specific ST segment and T wave changes.
On a flat plate of the abdomen, a large mass was noted on the left side of the upper abdomen. Following intravenous urography, the mass was seen to be above the left kidney, displacing it inferiorly and laterally. Retro- grade aortography revealed a pattern of vas- cular supply characteristic of an adrenal neo- plasm (Fig. 2). The mass was especially well-delineated by selective left renal and left phrenic arteriograms. Roentgenograms of the chest revealed several oval densities in both lung fields indicative of metastatic carcinoma. The ascending aorta was widened. A skeletal survey was unremarkable.
The urinary excretion of the neutral 17- ketosteroids was 105.7 mg/24 hours, of the 17-hydroxycorticoids (Porter-Silber) 16.5 mg/ 24 hours. Urinary gonadotropins were pres- ent in a titer of 5 and 10 mouse uterine units but absent at 100 mouse uterine units. The urinary excretion of the estrogens is given in Table 1. Estrogen production rates revealed the following values: estrone 3489 ug/24 hours; estradiol 2011 ug/24 hours; and estriol 8562 ug/24 hours (Table 2). The cortisol se- cretory rate was 8.0 mg/24 hours and that of 11-deoxycortisol was 13.5 mg/24 hours. Uri- nary testosterone excretion was 65.0 µg/24 hours. 16.4% of the intravenously adminis- tered androstenedione-3H was found to be converted into estrone and 15.2% into estriol. Conversion of testosterone-3H into estrone was 8.1%.
At exploration of the abdomen, a large nonresectable tumor adherent to the poste- rior parietes was encountered. These were multiple satellite nodules extending up un- der the diaphragm and down along the aorta. One of these nodules was excised. A testicular biopsy was also performed.
The pathologic report of the tumor nodule was partially necrotic adrenal cortical carci- noma. Very rare mitoses; no marked cellular atypism. The testes revealed marked atrophy of the tubules with hyalinization and arrest
of spermatogenesis at the spermatogonium stage. Many tubules were acellular and filled with vacuoles. There was interstitial fibrosis with absence of Leydig cells (Fig. 3).
The postoperative course was benign, and he was discharged 2 weeks postoperatively. He was seen again on an ambulatory basis about one month later. He felt quite well but complained of some swelling of the feet. One week later he suddenly died at home. No postmortem examination was obtained.
DISCUSSION
In this patient, as well as in the 8 other pa- tients in Table 3 (9-16), the pathologic di- agnosis was carcinoma. A survey of the clini- cal symptomatology and laboratory findings in the patients included in the present report does not, in general, alter the conclusions drawn from the initial study of 52 patients with this syndrome.10 It is of note that in the patient studied by Bacon and Lowrey,1 the original diagnosis was adenoma. The fre- quency of this error has been discussed in our previous report and is further highlighted by a personal communication from S. R. Hill in which he informed us that the patient orig- inally reported by Dempsey and Hill4 as hav- ing a feminizing syndrome due to a benign adrenocortical adenoma, recently presented in their clinic with metastases.
7
| ug/24 hrs | |
|---|---|
| Estrone | 602 |
| Estriol | 4978 |
| Estradiol | 28 |
| 16-hydroxyestrone | 141 |
| 16-ketoestradiol | 103 |
| 2-methoxyestrone | 2 |
| Epiestriol | 2 |
The increase in estrogen production in this patient (H.M.) is striking as is the increase in the urinary excretion of estrogen. It is of interest that in this patient the urinary ex- cretion of estrone and estriol was much higher than in the patient previously reported from this laboratory (P.F.).10 The urinary ex- cretion of estradiol was approximately the same in both and that of 16-hydroxyestrone and 16-ketoestradiol was less in H.M. as com- pared to P.F. It should be noted further that in H.M. the urinary excretion of testosterone was normal, being 65.0 µg/24 hours.
It would appear that the biological mani- festations are a result of alterations in the ratio of estrogen/androgen levels rather than in absolute values of testosterone or estro- gen.º
| Specific activities* | 3H/14C ratio | Production ratet | ||
|---|---|---|---|---|
| Estrone | 3H | 1320 | 6.2 | 3489 |
| 14C | 211 | |||
| 3H | 2905 | |||
| Estradiol | 13.9 | |||
| 14C | 145 | 2011 | ||
| He | 86 | |||
| Estriol | 10.5 | |||
| 14℃ | 910 | 8562 (from E1) | ||
* cpm/microgram t micrograms/24 hours
Note: 3H/14C ratio of injected E1/E2 = 7.9
This is borne out by the observation that the urinary excretion of estrogen may be markedly increased, and yet the clinical man- ifestations are those of virilization presum- ably because of a concomitant, even greater increase in androgen production.12 This is the probable explanation for the clinical pic- tures observed in the virilized patients re- ported by Loutfi and Emerson17 in whom high titers of urinary estrogen were found. Unfortunately, the urinary excretion of tes- tosterone was not assayed in any of these pa- tients. However, in a subject with a purely virilizing syndrome due to adrenocortical car- cinoma with disappearance of the menses whom we studied recently, the urinary ex-
| Case | Ref. # | Age (yrs) | Dx | Pain at tumor | Palpable tumor | Breast | Feminizing hair changes | Atrophy of testes | |
|---|---|---|---|---|---|---|---|---|---|
| Tenderness | Areolar pigmen- tation | ||||||||
| 53 Keller | 15 | 58 | Ca | yes | |||||
| 54 DeBella | 3 | 55 | Ca | yes | yes | yes | yes | ||
| 55 Bacon & Lowrey | 1 | 6 | Ca (original Dx adenoma) | yes | |||||
| 56 Kalinin | 14 | 23 | Ca | yes | yes | gynecomastia (2 yrs) | |||
| 57 Sakatoku et al. | 25 | 39 | Ca | no | yes | yes | yes | yes | |
| 58 Matsunaga | 19 | 51 | Ca | no | yes | yes | yes | ||
| 59 Solomon et al. | 31 | 31 | Ca | no | no | yes | yes | ||
| 60 Rose et al. | 24 | 55 | Ca | yes | yes | yes | no | ||
| 61 Gabrilove et al. | 55 | Ca | yes | yes | yes | yes | yes | ||
| Acnc | Libido diminished or absent | Potency diminished or absent | Blood pressure | Initial sign of symptoms | Course |
|---|---|---|---|---|---|
| yes | yes | 150/60 | palpable tumor, gynecomastia | Tumor 850 g | |
| yes | 140/80 | gynecomastia | Varicocele 3 yrs preop: Postop observation only 1 mo: 17-Ks fell and gynecomastia decreased | ||
| yes | 115/60 | gynecomastia; acne, pubic hair | Died 8 yrs postop; 9 yrs. after onset. Tumor weight 205 g. Bone age 12 yrs. Regression of gynecomastia postop for 4 yrs. No benefit from op'DDD | ||
| no | no | 130/80 | pain over tumor for 4 years | Gynecomastia for 2 yrs | |
| yes | yes | 135/95 | loss of libido | 3 year course prior to operation; large (1250 g) invading tumor. No recurrence in 2 yr follow-up | |
| decreased | 130/92 | fatigue | Short follow-up; improved after removal of tumor | ||
| yes | yes | 160/100 | headache, hypertension, gynecomastia | Temporary improvement. Died 6 years postop; op'DDD inefffective | |
| no | no | 100/68 | tender nipples, weight loss, flank pain | Died 1 year after onset | |
| yes | 140/80 | gynecomastia | Symptoms 3 years prior to Dx .; died 2 months postop |
| Ref. | Time | Chorionic gonadotropin | Pituitary gonadotropin/ 24 hrs | Estrogens (chemical) | Neutral 17-KS mg/24 hrs | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Estrogen (bioassay) | Total ug/24 hrs | Estrone ug/24 hrs | Estradiol ug/24 hrs | Estriol ug/24 hrs | ||||||
| Case | ៛ | |||||||||
| 53 | 15 | <10 | 1710 | 800 | 910 | 94 | ||||
| 54 | 3 | 53 | ||||||||
| 55 | 1 | preop | neg. at 6 | 8, 16, 20, 20, 20 R. U. | 28-53.5 | |||||
| postop | 6 | 5.2 R. U. | 1.9 | |||||||
| recurrence | 21.4-57.8 | |||||||||
| 56 | 14 | preop | 626 | 551 | 53 | 22 | 57.0 | |||
| postop | 64 | 12 | 8 | 44 | 3.4 | |||||
| 57 | 25 | preop | 73.5-318 | 146-163 | ||||||
| postop | 28.4 | 1.2-14.5 | ||||||||
| 58 | 19 | preop | Friedman neg. | 39.5 | 12 | 5 | 15 | 9.5 | ||
| postop | 15 | 7 | 1 | 7 | ||||||
| 59 | 31 | 0 | 11.5 µg estradiol | 13.2 | ||||||
| benzoate/24 hrs (nl 0.4-3.0) | (postop) | |||||||||
| 60 | 24 | preop | 3000 IU | 10.0 | ||||||
| postop | neg (< 750) | 8.0 | ||||||||
| 61 | +5, + 10 | 5856 | 602 | 28 | 4978 | 105.7 | ||||
| Neg 100 | ||||||||||
cretion of testosterone was 23.0 µg/24 hours, whereas the urinary excretion of estrogen was normal. In the patient studied by Harrison et al.,13 the virilization was limited to en- largement of the clitoris and amenorrhea. They believe that the minimal virilization encountered may have been due to the large quantities of estrogen produced in this pa- tient.
The testicular histology in H.M. comple- ments the studies we have reported previously 10, 30 in that the tubules were markedly hy- alinized and, in many instances, devoid of cells. In many of the tubules, maturation ar- rest of spermatogenesis at the spermatogo- nium stage was encountered. The Leydig cells were absent, and interstitial fibrosis was seen.
The conversion ratios of androstenedione
| Case | Ref. # | Time | 17-OH (Porter- Sliber) mg/24 hrs | 17-Ketogenic steroid mg/24 hrs | 11-Oxysteroid mg/24 hrs | Pregnanediol mg/24 hrs | Pregnanetriol mg/24 hrs | Remarks |
|---|---|---|---|---|---|---|---|---|
| 53 | 15 | 4.5 | 4.5 (nl < 2) | 12.0 (nl < 2) | DHA 38.6 (41 %) | |||
| A + E 28.1(30 %) 11-oxygenated 17-KS 20.1 (21 %) | ||||||||
| 54 | 3 | very large tumor | ||||||
| 55 | 1 | DHA 15.5-26.6 | ||||||
| (29-58 %) | ||||||||
| 56 | 14 | preop | 10.8-16.2 | 4.6 | 22.4 | DHA 2 | ||
| postop | 8.8 | 5.1 | 0.4 | 0 | ||||
| 57 | 25 | preop | 7.7 -24.7 | 7.7 | no effect on estrogen, | |||
| postop | 3.25-8.55 | 0.5 | pre- 17-KS or 17-OH by | |||||
| ACTH,PMS,DM; op DHA 2.14 mg | ||||||||
| 58 | 19 | preop | 6.2 | |||||
| 59 | 31 | preop | 44.2 | Urinary (Preop) | ||||
| postop | 13.7 | THS 5.1 mg | ||||||
| late postop | 13.7 | DOC 609 µg(increased) | ||||||
| Normal cortisol and | ||||||||
| corticosterone. Low | ||||||||
| aldosterone | ||||||||
| 60 | 24 | preop | 5.0 | |||||
| postop | 2.0 | |||||||
| 61 | 16 5 |
and of testosterone into estrogen in this pa- tient are extraordinarily high. Bolt and his associates found less than 1% of testosterone intravenously administered to men to be con- verted into estrogen.2 Similar findings were reported by MacDonald and Siiteri18 who also noted less than 1.8% of circulating 44- androstenedione to be converted into estro- gen. Unfortunately, because of the metastases and the inability to extirpate the tumor, it could not be ascertained whether the conver- sion of androstenedione and testosterone into estrogen occurred in the periphery or within the tumor. It seemed more likely to us that the tumor transformed these precursors into the excreted estrogens.
The low normal or low cortisol secretory rate, together with the high secretory rate of 11-deoxycortisol, is consonant with the re- ported observations of a decrease in the 11- hydroxylating capacities of these tumors10 and explains, as indicated in our previous re-
port, the lack of manifestations of Cushing’s syndrome by many of these patients.10 An in- creased production rate of 11-deoxycortisol or the increased urinary excretion of tetrahy- dro S is an important clue to the underlying presence of a malignant adrenocortical tu- mor,16 although similar changes are occasion- ally encountered with nontumorous hyper- functions as well as with benign adenomas.21
The difficulty of recognizing a feminizing syndrome in the postpuberal woman is sim- ilar to that of demonstrating a virilizing syn- drome in the postpuberal man. Four instances of feminizing adrenocortical tumors in female children have been reported.7, 22, 29, 32 Two of the tumors were adenomas and 2 carcinomas (Table 4). An instance of a so-called feminiz- ing tumor in a postmenopausal woman20 was complicated by concomitant evidences of vir- ilization and of Cushing’s syndrome-the fem- inizing symptom being postmenopausal vag- inal bleeding (Table 4).
| Snaith (1958)* | Wilkins (1965)= | Peluffo et al. (1962)2 | Ferrante et al. (1963)? | Monsaingeon et al. (1963)20 | |
|---|---|---|---|---|---|
| Age | 5 1/2 yrs | 3 yrs | 6 2/3 yrs | 26 mos | 65 yrs |
| Clinical manifestations | Pubic & axillary hair; breast development; vaginal bleeding; acne; adult vulva BP 110/80 Bone age: 12 years | Vaginal secretion; vaginal bleeding; accelerated bone age; pubic hair; adult size clitoris; breast development | Breast development; axillary & pubic hair; vaginal bleeding; painful abdominal mass; advanced bone age BP 90/60 | Breast enlargement 1 month; pubic hair; leukorrhea; hyper- trophy of labia minora; advanced bone age | Vaginal bleeding; obesity; hirsutism; hypertension |
| 17-KS* 1st adm. | 7.5-20.0/2.5-2.0 | 3.8/0.7 | 24-20/nl | 9.1 (high) | 64/ |
| mg/24 hrs 2nd adm. 17-OH* 1st adm. mg/24 hrs 2nd adm. | 2.8 | 41.1/.06 | |||
| 3.2-6.7/6.0-6.1 | 2.5 | 1.4 (nl) 10.9/1.27 | 5.4/ | ||
| Pregnanetriol* mg/24 hrs | 0/ | absent | |||
| Dehydroepi- androsterone* mg/24 hrs | principal 17-KS/ | 11-30/ | |||
| Estrogen E1* | 10.3-12.1/0 | ||||
| ug/24 hrs E :* | 3.8-5.1/0 | ||||
| E ;* | 4.4-16.0/0.8 | ||||
| 1st adm. Total* | 18.5-31.4/1.6 | 15-30nl | 18/ | ||
| 2nd adm | 54/ | ||||
| Gonadotropin | <2 R.U. | absent | |||
| X-ray | 2.5 × 2.5 X 9 cm Adenoma 10.7 g | presacral: tumor | Presacral: tumor on left side | Presacral: tumor | |
| Path. | (some anaplastic changes) | right cortical adenoma | Ca 1 Kg | Ca | Ca |
| Course | Regression of breasts and axillary and pubic hair | 3 yrs: normal decrease in pubic hair; Breast atrophy | Regression of symptoms postop (follow-up short) | Postop regression of breasts and normal hormonal excretion | Died 2 years after onset |
| Pregnanediol* mg/24 hrs | 0.7 (nl 0-0.1)/nl |
* preop/postop
Recent observations26 in this laboratory in regard to the production of androgen and es- trogen in the monkey adrenal are of interest in regard to feminizing tumors of the adrenal. The conversion ratio of androgen to estrogen was found to be greater in the adrenal cortex of female monkeys as com- pared to those of male monkeys, suggesting that the adrenal pathway and its conversion
ratio is analogous to that seen in the homolo- gous gonad and is perhaps genetically sex-con- trolled in the adrenal cortex as well as in the gonad. In tumors, however, these normal con- version ratios may be disturbed, permitting virilization of the female and feminization of the male, or preserved, as in the feminizing syndrome in the female or the virilizing syn- drome in the male.
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