ADRENOCORTICAL CARCINOMA WITH GYNECO- MASTIA: A CASE REPORT AND REVIEW OF THE LITERATURE
STANLEY WALLACH, M.D .* , HAROLD BROWN, M.D., EDWIN ENGLERT, JR., M.D.t AND KRISTEN EIK-NES, M.D.
The Departments of Medicine and Biochemistry, University of Utah College of Medicine and the Veterans Administration Hospital, Salt Lake City, Utah
T HE development of gynecomastia is an uncommon result of excessive steroid hormone production by adrenocortical tumors. The present re- port concerns the thirty-fourth occurrence of this phenomenon recorded in the world literature (1-16). The findings of relative adrenocortical insuf- ficiency, increased excretion of estrogen-like materials in the urine and the successful isolation of steroids from the tumor (17) are of special interest in this patient.
CASE REPORT
A 28-year-old radio announcer noted the onset of intermittently tender nipples in March 1953 and of bilateral breast enlargement in September 1953. There was pro- gressive increase in size during the next twelve months. The patient was sufficiently embarrassed by this cosmetic defect to request admission to the Salt Lake Veterans Administration Hospital in March 1955 for evaluation and treatment.
He had noted a very gradual decline in libido and potency during the two years prior to admission. There were no other symptoms and no fluctuations in weight. The past history was negative. There was no history of gynecomastia during puberty, or of jaundice, liver disease, alcoholism or exposure to hepatoxins or estrogens.
The patient had a 2-year-old child. Contraception had been employed for two years prior to hospitalization.
Physical examination revealed a young, thin white male who appeared in good health. His voice was deep and masculine. The blood pressure varied from 120/60 to 160/100, the pulse was 84 per minute, respirations 15 per minute and temperature 98.6º F. The skin was clear. Pubic and axillary hair were present in moderate amounts and the pubic hair had a feminine distribution. The beard was sparse.
Examination of the head and neck, lymphatic system, heart, lungs, extremities, rectum and neurologic system yielded negative results. The abdomen was free of pal- pable masses or enlarged organs. The breasts were considerably enlarged (Fig. 1), with palpable subareolar glandular tissue, deeply pigmented, non-tender nipples and prom- inent Montgomery tubercles. The testes measured 1.5 to 2 cm. in diameter and were smooth and firm. The penis and prostate were normal.
Laboratory data. The volume of packed red blood cells was 41 ml. per 100 ml. of
Received October 15, 1956.
* Present address: Massachusetts General Hospital, Boston, Mass.
t Fellow, USPHS. Present address: Massachusetts Memorial Hospital, Boston, Mass.
A
B
blood. The leukocyte count was 6,650 per cu.mm. with 67 per cent neutrophils, 31 per cent lymphocytes, 1 per cent monocytes and 1 per cent eosinophils. A peripheral blood smear revealed normochromic, normocytic erythrocytes and adequate platelets. Results of urinalysis were negative. The blood urea nitrogen level was 5.7 mg. per 100 ml. The concentration of serum sodium was 151 mEq./L., chloride 109 mEq./L., potassium 3.4 mEq./L. and bicarbonate 27 mEq./L. The concentration of serum total protein was 5.9 grams per 100 ml., of which 4.4 grams was albumin. The total serum bilirubin level was 0.6 mg. per 100 ml., with 0.1 mg. of direct-reacting bilirubin per 100 ml. The serum thymol turbidity was 3.5 units and the serum alkaline phosphatase level 1.8 Bodansky units per 100 ml. The concentration of serum cholesterol was 164 mg. per 100 ml. Serum bromsulfophthalein retention at forty-five minutes was 1 per cent. The serum protein-bound iodine level was 4.1 ug. per 100 ml.
An oral glucose tolerance test showed a fasting blood sugar concentration of 79 mg. per 100 ml. with values of 95, 82, 71 and 100 mg. per 100 ml. at a half hour, one hour, two hours, and three hours, respectively, after ingestion of 50 grams of glucose. During an intravenous glucose tolerance test utilizing a thirty-minute infusion of 0.5 Gm. of glucose per Kg. of body weight, the maximum blood sugar concentration was 184 mg. per 100 ml. at the end of the infusion, with a return to a level of 80 mg. per 100 ml. one hour later. No hypoglycemia followed either test.
Seminal fluid obtained by ejaculation was turbid and watery. The sperm count was 1.7 million per ml. Forty per cent of the sperm were motile and less than 5 per cent were atypical.
Roentgenograms showed a normal chest, skull, pelvis and long bones. Upon abdom-
inal x-ray examination, there was a suggestion of a mass in the right upper quadrant. A combined intravenous pyelogram and presacral air insufflation study demonstrated a large ovoid mass above the right kidney, displacing the kidney inferiorly and the liver anteriorly (Fig. 2).
The Friedman test for chorionic gonadotropin in the urine yielded negative results. Upon bioassay for urinary follicle-stimulating hormone (FSH) performed by the method of Salhanick (18), there was no detectable FSH. In human adult males, the normal range is 2 to 3 Armour units.
Urinary 17-ketosteroid excretion (19) varied from 8.6 to 13.2 mg. per twenty-four hours (normal range, 10 to 15 mg.). Urinary 17-hydroxycorticosteroid excretion (20) varied from 4.5 to 7.1 mg. per twenty-four hours (normal range in this laboratory, 1.0 to 7.7 mg.).
The plasma free 17-hydroxycorticosteroid (17-OHCS) level (21) at eight o’clock in the morning varied from 15 to 18 ug. per 100 ml. Serial measurements of plasma free 17-OHCS during a 24-hour period revealed a progressive decline from 16 ug. per 100 ml. in the early morning to a minimum value of 8 ug. per 100 ml. at midnight. A rapid rise in the concentration of plasma free 17-OHCS occurred after four o’clock in the morning. The mean level of plasma free 17-OHCS for normal persons at eight o’clock in the morning in our laboratory is 12.5+3.7 ug. per 100 ml., and a diurnal variation similar to that described for the patient is seen in normal individuals (22).
Tests of response to corticotropin (ACTH) and cortisol removal were performed in
accordance with previously described protocols (23, 24). Figure 3 depicts the patient’s responses to six-hour infusions of 25 units of ACTH administered at various times during an eighteen-month period. Prior to surgery, there was no rise in the level of plasma free 17-OHCS, in contrast to an approximate threefold rise in normal persons. The cortisol removal test revealed a mod- ACTH RESPONSE erate delay in the disappearance of plasma free 17-OHCS after a standard thirty- minute infusion of 1 mg. of cortisol per 30 20 Kg of body weight.
MARCH 1955 PREOPERATIVE
10
30
20
APRIL 1955 POSTOPERATIVE
PLASMA 17-OHCS Y/ 100 ml
10
40
3)
JUNE 1955
20
2 MONTHS ACTH THERAPY
10
30
20
SEPTEMBER 1955 NO ACTH TREATMENT
10
30
JANUARY 1956 OCCASIONAL ACTH TREATMENT NONE FOR ONE MONTH
20
10
30
20
MAY 1956
NO ACTH TREATMENT
10
HOURS
2
4
6
Bioassay for urinary estrogens was per- formed by Dr. R. K. Meyer of the Univer- sity of Wisconsin, utilizing a modification of the vaginal cornification technique of Allen and Doisy (25). The urinary estro- gen content varied from 73 ug. to 177 ug. of estrone equivalent per twenty-four hours. The normal range for adult males is from 2 to 29 µg.
Operation. On the fourteenth hospital day, Dr. J. A. Gubler explored the patient’s abdomen through a right flank incision. Because of poor augmentation of adreno- cortical secretion of 17-OHCS by exogenous ACTH (Fig. 3), 150 mg. of cortisone was given on each of the two days prior to operation, and 100 mg. of cortisol was ad- ministered intravenously during surgery. A large solid tumor occupied the right suprarenal area. No evidence of local in- vasion or intra-abdominal metastases was found and the opposite adrenal was normal to palpation. Excision was performed with- out incident.
The tumor was a firm encapsulated oval mass, weighing 920 grams (Fig. 4). Numerous large veins traversed the thick fibrous capsule. A cut section showed a lobular contour with bulging of the tumor tissue above the cut surface. The tumor was predominantly grey-brown in color with some dark brown and yellow areas. There were small foci of necrosis and two small cysts.
On microscopic examination, the tumor consisted of sheets, nests and cords of pleomorphic epithelial cells. Many cells were small and regular with oval, pale, bluc- staining nuclei. Others were large and polyhedral with abundant cytoplasm and hyper- chromic, often multilobed nuclei. Multinucleate cells were not uncommon. In certain areas, invasion of the fibrous capsule and of the walls of capsular veins was seen (Fig. 5).
Explantation of tumor cells into the anterior chamber of the eyes of 4 guinea pigs resulted in gross proliferation of the tumor. Pathologic diagnosis by Dr. O. N. Rambo was cortical carcinoma of the right adrenal gland with evidence of invasion of capsular veins.
The steroid content of the tumor was determined by Drs. Salhanick and Berliner (17). They identified two compounds, progesterone and equilenin, in concentrations of 850 and 580 µg. per 920 Gm. of tumor, respectively. Six other steroids were isolated in
August, 1957 ADRENOCORTICAL CARCINOMA WITH GYNECOMASTIA 949
lesser amounts, but precise identification of these latter six compounds was not possible. Some were shown to be phenolic, thus having benzenoid A rings. These were not estradiol, estriol or estrone. Other compounds among the unidentified group were 17-ketosteroids. These findings are to be reported in detail elsewhere (17).
The postoperative course was uneventful. Moderate doses of cortisone and, later, cortisol were given during the first and second postoperative weeks. The dosage of cortisol was gradually reduced and finally discontinued in the third postoperative week. ACTH-gel was administered during the last four days of steroid therapy.
The patient resumed full activity four weeks after operation. Physical and roentgen examinations eighteen months after surgery revealed no evidence of recurrence or metastases. The gynecomastia had regressed completely. The breasts were slightly prominent but no glandular tissue was palpable (Fig. 1). The testes had doubled in size and the sperm count had gradually increased to 26 million per ml., with normal motility and structure. The physical findings were unchanged two years after surgery despite the appearance of pulmonary metastases.
A postoperative corticotropin test revealed continued poor adrenocortical response to ACTH (Fig. 3). Intensive therapy with corticotropin for the next two months re- sulted in a return to a normal response with this test. However, when corticotropin was discontinued for three months, a reversion to a suboptimal response occurred. Fourteen months and eighteen months after surgery, a twofold increment occurred in the plasma free 17-OHCS level after six hours of stimulation with corticotropin.
DISCUSSION
A summary of the clinical and biochemical features of the 34 reported cases of feminizing adrenocortical carcinoma is presented in Tables 1 and 2. Four cases prior to 1948 (2, 3, 4, 16) were not included in Wilkins’ review of 12 patients (1). Cahill’s patient (2) had a typical history, and a markedly enlarged left adrenal shadow was demonstrated by perirenal air insuffla- tion. Hurxthal and Musulin (3) thought their patient had “a tumor of mixed renal origin.” However, the pathologic findings, clinical features and the positive results of estrogen bioassay are more compatible with a feminizing adrenocortical carcinoma. Östergaard’s patient (4) had a tumor in the scrotum which was anatomically separate from the homolateral, atrophic testis. It resembled an adrenocortical carcinoma rather than a testicular tumor.
Seventeen acceptable cases have been reported since 1948 (5-16). Chambers’ patient (26) is not included because he more likely had a meta- static choriocarcinoma of the testis. In his case, serial sections of the testes were not made in order to rule out a microscopic primary choriocarcinoma (see reference 27).
The symptoms and physical findings in the reported patients have been remarkably uniform. Gynecomastia often preceded other symptoms by many months. Occasionally, symptoms due to the mechanical effects of a large tumor or the presence of reduced libido and potency were the chief complaints. In these patients, gynecomastia was usually present on ex-
August, 1957 ADRENOCORTICAL CARCINOMA WITH GYNECOMASTIA 951
| Case report and reference | Age of pa- tient (yrs.) | Clinical findings | ||||
|---|---|---|---|---|---|---|
| Pal- pable tu- mor | Gyn- eco- mas- tia | Tes- ticu- lar atro- phy | Re- duced libido & po- tency | |||
| 1. | Bittorf, Mathias (1) | 26 | + | + | + | + |
| 2. | Zum Busch, Parkes- Weber (1) | 27 | 0 | + | ||
| 3. | Holl (1) | 15 | + | + | 0 | |
| 4. | Holl (1) | 44 | 0 | + | + | + |
| 5. | Lisser (1) | 33 | + | + | ||
| 6. | Simpson & Joll (1) | 34 | + | + | + | + |
| 7. | Pico Estrada (1) | 30 | + | + | ||
| 8. | Pico Estrada (1) | 41 | + | |||
| 9. | Kooyman (16) | 29 | + | + | + | + |
| 10. | Cahill et al. (2) | 53 | 0 | + | + | + |
| 11. | Roholm & Teilum (1) | 44 | + | + | + | -+- |
| 12. | Hurxthal & Musulin (3) | 38 | + | + | + | + |
| 13. | McFadzean (1) | 29 | + | + | 0 | + |
| 14. | Östergaard (4) | 28 | + | + | + | 0 |
| (scro- | ||||||
| 15. | Scott (1, 16) | 43 | tal) | + | + | + |
| 16. | Wilkins (1) | 5 | 0 | + | 0 | |
| 17. | Armstrong & Simp- son (5) | 40 | + | + | 0) | |
| 18. | Staffieri et al. (6) | 25 1 | + | + | 0 | |
| 19. | Luft & Sjögren (16) | 59 | 0 | + | 0 | |
| 20. | Mortensen & Mur- phy (7) | 38 | 0) ! | + | + | + |
| 21. | Diezfalusy & Luft (8) | 55 | + | + | ||
| 22. | Myhre (9) | 37 ₾ | + | + | + | + |
| 23. | Nusimovish (16) | 40 | + | + | + | + |
| 24. | Pickard et al. (16) | 14 1 | + | + | + | |
| 25. | Curr & Vines (16) | 47 | + | + | + | + |
| 26. | Dohan et al. (10) | 30 | 0 | + | + | + |
| 27. | Dohan et al. (10) | 58 | + | + | + | |
| 28. | Landau et al. (11) | 28 | 0) | + | + | 0 |
| 29. | Seror et al. (12) | 56 | + | + | 0) | + |
| 30. | Staubitz et al. (13) | 38 | + | + | + | |
| 31. | Case Record, Mass. Gen. Hosp. (14) | 66 | + | + | 0 | + |
| 32. | Dostal (15) | |||||
| 33. | Higgins et al. (16) | 26 | 0 | + | + | + |
| 34. | Wallach et al. (pres- ent case) | 28 | 0 | + | + | + |
Remarks
No treatment. Died of metastases 11 mos. after onset of symptoms
No treatment. Died of metastases 3 mos. after onset. of symptoms
Tumor inoperable at exploration 2 mos. after onset of symptoms. Died a few wks. after surgery
Tumor excised 2 yrs. after onset of symptoms. Re- gression of symptoms & no recurrence 6 mos. after surgery
No treatment. Died of metastases 2 mos, after onset of symptoms
Tumor excised 2 yrs. after onset of symptoms. Post- op. radiation. Recurrence & death from metastases 2 yrs. after surgery
No treatment. Died of metastases
No treatment. Died of metastases
Tumor inoperable at exploration 3 yrs. after onset of symptoms. Died on first postop. day
Symptoms present 3 yrs. Patient refused therapy or follow-up
No treatment. Died of metastases 4 yrs. after onset of symptoms
Radiation therapy. Died of metastases 2 yrs. after on- set of symptoms
Tumor excised 18 mos. after onset of symptoms. Fol- low-up restricted to 6 wks. after surgery
Tumor excised 2 yrs. after onset of symptoms. No recurrence of symptoms or tumor 2 yrs. after surg- ery
Tumor excised 3 mos. after onset of symptoms. Died of metastases 9 mos. after onset of symptoms Tumor excised 4+ yrs. after onset of symptoms. No recurrence 4 yrs. after surgery
Tumor inoperable at exploration 6 mos. after onset of symptoms. Died of metastases 5 mos, after surgery Tumor excised 2 mos. after onset of symptoms. Post- op. radiation. No recurrence 2 yrs. after surgery
Tumor excised 5 mos. after onset of symptoms. Died on second postop. day
Tumor excised 18 mos. after onset of symptoms. No recurrence 5 mos. after surgery
Tumor excised 1 yr. after onset of symptoms. Died of metastases 8 mos. after surgery
No treatment. Died of metastases 7 yrs. after onset of symptoms. Unrelated carcinoma of the prostate
Tumor inoperable 7 mos. after onset of symptoms. Died of cachexia after 1 yr. of symptoms
Radiation therapy. Died of metastases 1 yr. after on- set of symptoms
Died during postop. period, 3 yrs. after onset of symptoms
Tumor excised “a few months” after onset of symp- toms. No recurrence 18 mos. after surgery
Tumor excised 1 yr. aft. D’ 16 mos. after surgery of u. :
- moma. No evidence of recurrence of adrenal tumor at autopsy
Tumor excised 16 yrs. after onset of symptoms. No recurrence 1 yr. after surgery
Tumor excised 9 mos. after onset of symptoms. Fol- low-up restricted to 3 mos. after surgery
Alive with metastases 54 yrs. after onset of symptoms Tumor incompletely excised 10 mos. after onset of symptoms. Recurrence 15 mos. after surgery. Died 3 yrs. after onset of symptoms
No further information available
Tumor incompletely excised 10 mos. after onset of symptoms. Radiation & nitrogen mustard therapy.
Died of metastases 16 mos. after onset of symptoms Tumor excised 2 yrs. after onset of symptoms. Recur- rence 2 yrs. after surgery
| Case report and reference* | Urine | Identification of urinary steroids | Remarks | ||||
|---|---|---|---|---|---|---|---|
| Chorionic Gonadotropin | Pituitary Gonadotropint | Estrogen t (bioassay) | Androgent (bioassay) | 17-KS (mg./24 hrs.) | |||
| 6. Simpson & Joll (1) | Negative (A-Z test) | 3200 m.u./24 hrs. ("Pathologie excess") | 60 c.c.u./24 hrs. (Normal 8-25 c.c.u.) | A3-5, Androstandiene-17- one | Studies performed after exci- sion of tumor but in pres- ence of metastases | ||
| 10. Cahill et al. (2) | Normal glucose tolerance, pigmentation, hypotension | ||||||
| 11. Roholm & Teilum (1) | Negative (Friedman test) | <30 R. U. /24 hrs. (Normal <30 R.U.) | 5000 m.u./24 hrs. (Normal <20 m.u.) | 164 c.c.u./24 hrs. (Normal 8-25 c.c.u.) | Normal glucose tolerance | ||
| 12. Hurxthal & Musulin (3) | 60 R. U. /24 hrs. (Normal <10 R.t.) | : | |||||
| 13. McFadzean (1) | Pos. (A-Z test) | Flat glucose tolerance curve | |||||
| 14. Öster gaard (4) | Negative (Friedman test) | <50 m.u./24 hrs. | 200 m.u. /24 hrs. ("Increased excretion") | 25 r.c./24 hrs. | After excision of tumor, uri- nary pituitary gonadotro- pin, 50 m.u .; estrogen, 50 m.u .; androgen, 62 1.U./24 hrs. | ||
| 15. Scott (1, 16) | 5.3 ug.a-estradiol equiv./24 hrs. (Normal) | 196.0 | Dehydroisoandrosterone. 70 mg. 24 hr -. | After excision of tumor, uri- nary 17-ketosteroid, 9.6 mg./24 hrs .; estrogen, 9.6 ug. a-estradiol equiv./24 hrs. | |||
| 16. Wilkins (1) | <6.5 m.u. /24 hrs. | 5 R.U./24 hrs. "Slightly above (normal") | 4.1 | No urinary pregnanediol | |||
17. Armstrong & Simpson (5)
34-108
18. Staffieri et al. (6)
23.2
Severe reactive hypogly- cemia
* Numbered according to the listing in Table 1.
f R. C. = Rat units.
m.u. = Mouse units.
I.C. = International units
c.c.u. = Capon-comb units.
| Case report and reference* | Urine | Identification of urinary steroids | Remarks | ||||
|---|---|---|---|---|---|---|---|
| Chorionic Gonadotropin | li ti ary Gont do. ropint | Estrogent (bioassay) | Androgent (bioassay) | 17-KS (mg./24 hrs.) | |||
| 19. Luft & Sjögren (16) | <20 m.u./24 hrs. | 250 I.C./24 hrs. | 6.0 | Hypertension, diminished glucose tolerance, insulin resistance. Bilat. adreno- cortical hyperplasia & uni- lat. neoplasm | |||
| 20. Mortensen & Murphy (7) | Neg. (A-Z test) | 7.6 | Flat glucose tolerance curve. Hyponatremia | ||||
| 21. Diczfalusy & Luft (8) | Free estriol, 34.5 ug./250 ml. urine Conjugated estriol, 857 ug./ 250 inl. urine Conjugated estrone, 68.5 µg. /250 ml. urine Conjugated estradiol, 18.4 µg. /250 ml. urine Pregnanediol, 29.0 mg./L. | ||||||
| 22. Myhre (9) | Negative (Friedman test) | <33 m.u./liter | 256.0 | Normal glucose tolerance | |||
| 23. Nusimovish (16) | 48-96 units#/liter | 5000 unitst/liter | 6.9 | Method and units not stated | |||
| 24. Pickard, et al. (16) | 160 1.U./24 hrs. | 22-39 | Pregnanediol, 49.5 mg./24 hrs. : | Hypertension. Normal glu- cose tolerance. Urinary 11- oxysteroids, 26 mg./24hrs. | |||
| 26. Dohan et al., Case 1 (10) | 24 m.u./24 hrs. | 4000 m.u./24 hrs. (Normal 13-44 m.u.) | 12.4 | Hypertension. Normal glu- cose tolerance. Urinary cor- ticoid, 4.0 mg. /24 hrs. (nor- mal, 2.0-5.0 mg./24 hrs.). After excision of tumor, hypertension relieved; uri- nary estrogen, 27 m.u./24 hrs. | |||
| 27. Dohan et al., Case 2 (10) | 460 m.u./24 hrs. (Normal 13-44 m .u.) | 5.8 | Estrogen determined 2 days after excision of tumor; 6 mos. later urinary estro- gen, 13 m.u./24 hrs. | ||||
# Normal range not stated.
| Case report and reference* | Urine | Identification of urinary steroids | Remarks | ||||
|---|---|---|---|---|---|---|---|
| Chorionic Gonadotropin | Pituitary Gonadotropint | Estrogent (bioassay) | Androgent (bioassay) | 17-KS (mg./24 hrs.) | |||
| 28. Landau et al. (11) | 30.0 | HCI hydrolysis: Estriol, 57 ug./24 hrs. Estrone, 86 µg. /24 hrs. Estradiol, 15 µg. /24 hrs. Zn-HCI hydrolysis: Estriol, 74 ug./24 hrs. Estrone, 8 ug. /24 hrs. Estradiol, 114 µg. /24 hrs. Pregnanediol, 1.9 mg./24 hrs. | Normal results with water loading tesu Urinary formaldehydogenic cor.icoids, 0.94 mg. /24 hrs. (normal) After excision of tumor, uri- nary estriol, 13 µg. /24 hrs .; estrone 9 µg./24 hrs .; es- tradiol, 10 µg./24 hrs. (HCI hydrolysis). Postop. urinary pregnanediol 0.03 mg./24 hrs. | ||||
| 29. Seror et al. (12) | 9.2 | ||||||
| 30. Staubitz, et al. (13) | Negative (A-Z test) | <3.2 m.u./24 hrs. | 3340 I.t./24 hrs. (Normal 25-130 I.U.) | 26-55 | All data obtained after ex- cision of tumor but in pres- ence of metastases | ||
| 31. Case record, Mass. Gen. Hosp. (14) | <8 m.u./100 cc. (neg.) | <6.5 m.u./24 hrs. | 1235 µg. "estro- gen" ("Normal 40- 80 µg.) | 510.0 | Dehydroisoandrosterone, 300 mg. Etiocholanolone Androsterone 11-hydroxyandrosterone | After excision of tumor, uri- nary estrogen 80 µg. /24 hrs. 17-ketosteroids, 16 mg./ 24 hrs. After recurrence, 17-ketosteroids, 38-45 mg. /24 hrs. | |
| 33. Higgins, et al. (16) | Negative (Friedman test) | 96 m.u./24 hrs. | 2600-6200 µg./24 hrs. | 150-600 | Pregnanediol. 86.6-622.0 mg./24 hrs. | Normal glucose tolerance. Urinary 11-oxysteroids, 3.4 mg. /24 hrs.# Analysis of tumor: estrogen (Kober reaction) 280 mg./ /70 Gm. of tumor tissue; pregnanediol (Guterman reaction), 4 mg. /70 Gm. of tumor tissue; 17-ketos- teroids, 3.1 mg./70 Gm. of tumor tissue | |
| 34. Wallach et al. (present case) | Negative (Friedman test) | 0 | 73-177 µg. estrone equiv./24 hrs. (Normal 2-29 µg.) | 8.6-13.2 | Flat glucose tolerance curve; relative adrenocortical in- sufficiency. Progesterone, equilenin & 6 unidentified compounds isolated from tumor | ||
August, 1957 ADRENOCORTICAL CARCINOMA WITH GYNECOMASTIA 955
amination. In one remarkable report (6), recurrent coma due to reactive hypoglycemia was the presenting symptom. In an occasional patient obesity, acne, hirsutism or pigmentation developed in association with feminization. In only 1 patient, that of Luft and Sjögren (cited in reference 16), were there more definitive stigmata of adrenocortical dysfunction. This patient manifested hypertension, diminished glucose tolerance and insulin resistance as well as the expected gynecomastia and testicular atrophy. Exploration revealed the unusual finding of bilateral adrenocortical hyper- plasia and a unilateral adrenocortical tumor.
A flat glucose tolerance curve was noted in 3 of 9 patients tested. The present patient had a flat oral glucose tolerance curve and a feeble re- sponse to stimulation with corticotropin, suggesting the presence of rela- tive adrenocortical insufficiency. The patient with reactive hypoglycemia, however, did not have a flat glucose tolerance curve.
The cellular pathology of the tumors of the reported cases was extremely variable. Many benign-appearing tumors developed widespread metas- tases, resulting in early death of the patient. Other tumors were clearly malignant by the usual criteria but appeared to carry a prognosis no worse than that of less anaplastic tumors. Inasmuch as metastases developed in 19 of the 34 patients cited, all adrenocortical tumors with gynecomastia should be considered malignant.
Endocrinologic aspects
The production of biologically active estrogens by these tumors has been well documented. Increased amounts of estrone, estriol, estradiol and pregnanediol have been found in the urine in 2 recent cases (8, 11). This suggests that the activity of many of these tumors is directed toward the production of steroids with benzenoid A rings (presumably estrogenic) and toward the production of progesterone. The identification of progesterone and some phenolic steroids with benzenoid A rings in the tumor of the present case strongly supports this view (17). The isolation from this tumor of equilenin (17), a weakly estrogenic steroid with benzenoid A and B rings, is of considerable interest, since this hormone has not been previ- ously identified in man.
The laboratory evidence of adrenocortical hypofunction seen in some of these cases is most probably due to the suppression of pituitary produc- tion of corticotropin by one or more abnormal circulating steroids. As in the present case, this suppression persists for months after the tumor is re- moved. In the few instances in which Cushing-like characteristics have been described in addition to the feminization, the tumors were probably secreting steroids with 17-OHCS-like function as well as estrogens. In Luft and Sjögren’s patient (16), the hyperplastic, nontumorous adrenal cortices
may have been the site of production of steroids with 17-OHCS-like action. The production of both estrogens and androgens by adrenocortical tumors has also been reported (1, 10). Feminization may not be present if androgen secretion predominates.
Small changes in the A ring and of the substituent groups on the per- hydrocyclopentanophenanthrene nucleus have been found to result in great changes in physiologic action. It is reasonable to assume that the ac- tions of the steroid hormones which produce feminization and masculiniza- tion may depend upon minor changes in the molecule. Scott’s patient (1, 16) had gynecomastia and other evidence of feminization but there was no increase in urinary estrogen when measured by the usual bioassay methods. A greatly increased urinary 17-ketosteroid excretion was noted and large amounts of dehydroisoandrosterone, a metabolite of testosterone, were found. Dehydroisoandrosterone and related compounds have been found capable of inducing gynecomastia in laboratory animals (28), and the feed- ing of large amounts of testosterone to animals and man has resulted in increased urinary estrogens (29).
Cases of feminizing adrenocortical tumor in which elevated estrogen ex- cretion was accompanied by very high 17-ketosteroid excretion or elevated titers of biologically active androgen, may not necessarily represent situa- tions wherein two or more different types of steroids are being produced. It is possible that a steroid with one type of biologic and chemical property may undergo partial conversion in some other tissue to other steroids with distinctly different actions, resulting in a wide variety of biologic and chemical findings. Actual identification of the steroids in the tumor tissue and urine from patients with adrenocortical hyperplasia and neoplasms, and collateral studies of the biologic and chemical effects of pure steroids administered to human subjects and experimental animals are needed to elucidate this problem.
SUMMARY
1. The thirty-fourth reported case of a feminizing adrenocortical car- cinoma is described. Gynecomastia was the presenting complaint in this patient.
2. Endocrinologic studies revealed elevated urinary excretion of estro- gen, normal excretion of 17-ketosteroids, absence of both chorionic gonado- tropin and follicle-stimulating hormone in the urine, a flat glucose tolerance curve, and a response to the corticotropin (ACTH) test which was indica- tive of relative adrenocortical insufficiency.
3. Pulmonary metastases developed two years after excision of the carci- noma. Prior to recurrence, all abnormal findings had regressed and the sperm count had risen from 1.7 to 26 million per ml.
August, 1957 ADRENOCORTICAL CARCINOMA WITH GYNECOMASTIA 957
4. The tumor contained moderate concentrations of progesterone and of equilenin, a weakly estrogenic steroid not previously found in human sub- jeets. Six other unidentified steroids were also isolated (17).
REFERENCES
1. WILKINS, L .: A feminizing adrenal tumor causing gynecomastia in a boy of five years contrasted with a virilizing tumor in a five-year-old girl. Classification of seventy cases of adrenal tumor in children according to their hormonal manifesta- tions and a review of eleven cases of feminizing adrenal tumor in adults, J. Clin. Endocrinol. 8: 111, 1948.
2. CAHILL, G. F .; MELICOW, M. M., and DARBY, H. H .: Adrenal cortical tumors, Surg., Gynec. & Obst. 74: 281, 1942.
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11. LANDAU, R. L .; STIMMEL, B. F .; HUMPHREYS, E., and CLARK, D. E .: Gynecomastia and retarded sexual development resulting from a long-standing estrogen-secreting adrenal tumor, J. Clin. Endocrinol. & Metab. 14: 1097, 1954.
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13. STAUBITZ, W. J .; OBERKIRCHER, O. J .; LENT, M. H .; BISSELL, G. W., and FARNS- WORTH, W. E .: Feminization in an adult male with adrenal cortical carcinoma, New York State J. Med. 54: 2565, 1954.
14. Case Records of the Massachusetts General Hospital: New England J. Med. 252: 496, 1955.
15. DOSTÁL, M .: Feminisující nezhoubný nádor nadledvinek (Feminizing benign sur- renal tumor), Vnitř. lek., Brno 1: 245 (Apr.) 1955. (Cited in Current List Med. Lit., A. F. Med. Library, Washington, Vol. 28, Nov. 1955, item 59418.)
16. HIGGINS, G. A .; BROWNLEE, W. E., and MANTZ, F A .: Feminizing tumors of the adrenal cortex, Am. Surgeon 22: 56, 1956.
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18. SALHANICK, H .: In preparation.
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of substances containing the grouping-CH2. CO-in urine extracts as an indication of androgen content, Biochem. J. 32: 1312, 1938.
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23. EIK-NES, K .; SANDBERG, A. A .; NELSON, D. H .; TYLER, F. H., and SAMUELS, L. T .: Changes in plasma levels of 17-hydroxycorticosteroids during the intravenous ad- ministration of ACTH. I. A test of the adrenocortical capacity in the human, J. Clin. Invest. 33: 1502, 1954.
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25. ALLEN, E., and DoIsY, E. A .: An ovarian hormone: a preliminary report on its localization, extraction, and partial purification, and action in test animals, J. A.M.A. 81: 819, 1923.
26. CHAMBERS, W. L .: Adrenal cortical carcinoma in a male with excess gonadotropin in the urine, J. Clin. Endocrinol. 9: 451, 1949.
27. Clinico-pathologic Conference: Mediastinal tumor with gynecomastia and superior vena caval obstruction, Am. J. Med. 6: 247, 1949.
28. PINCUS, G., and THIMANN, K. V .: The Hormones. Physiology, Chemistry and Applications. New York, Academic Press Inc., 1948, p. 729.
29. Ibid., p. 525.
KEM