Feminizing Adrenocortical Carcinoma with Hypertension
SOLOMON S. SOLOMON,’ STEPHEN P. SWERSIE, AND C. ALVIN PAULSEN,
Division of Endocrinology, USPHS Hospital, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98114,
AND EDWARD G. BIGLIERI,
Medical Service, San Francisco General Hospital, and Department of Medicine, University of California School of Medicine, San Francisco, California
ABSTRACT. A case report is presented de- scribing a male who had hypertension associated with a feminizing adrenocortical carcinoma. A marked elevation in the secretory rate of DOC was observed which suggests that an 118-hy-
droxylatior. block in this syndrome is causally related to the hypertension. The long survival of over 6 yr and the results of treatment with o,p’- DDD are discussed. (J Clin Endocr 28: 608, 1968)
F EMINIZING adrenocortical tumors in males are uncommon. Furthermore, survival beyond three years is rare. Gabri- love et al. (1) reviewed 51 cases from the literature and added an additional patient. In addition to their report, three other cases have been documented (2-4). Hyper- tension may be an integral part of the clinical picture in these patients. West et al. (5) postulated that increased production of deoxycorticosterone (DOC)? might be responsible for the development of the
Received July 18, 1967; accepted December 24. Supported by Grants AM 05436, AM 05161 and AM 06415, NIH. Steroid studies were performed at the General Clinical Research Center FR-83, San Francisco General Hospital, supported by the Division of Research Grants and Facilities, NIH. 1 USPHS Fellowship 5-F2-AM-30 112-02.
2 Trivial names for steroids: DOC =21-hydroxy- pregn-4-ene-3,20-dione; THS, tetrahydro-11-deoxy- cortisol = 3a,17a,21-trihydroxy-58-pregnan-20- one; THE, tetrahydrocortisone = 3a,17a,21-tri- hydroxy-56-pregnane-11,20-dione; THF, tetrahy- drocortisol = 3a,118,17a,21-tetrahydroxy-56-preg- nan-20-one; 17a-hydroxyprogesterone = 17a-hy- droxy-pregn-4-ene-3,20-dione; 116-hydroxyestrone =3,118-dihydroxyestra-1,3,5(10)-trien-17-one; es- tradiol = 3,178-dihydroxyestra-1,3,5(10)-triene; aldosterone = 118,21-dihydroxy-18-oxo-pregn-4- ene-3,20-dione; hydrocortisone = 118,17a,21-tri- hydroxypregn-4-ene-3,20-dione; dexamethasone = 118,17a,21-trihydroxy-9a-fluoro-16a-methylpregna- 1,4-diene-3,20-dione.
hypertension in these cases. The following case report describes the clinical and laboratory findings in a 31-year-old male with feminizing adrenocortical carcinoma and hypertension, who survived 6} years from the onset of his symptoms. Elevated urinary tetrahydro S (THS) levels were present along with an increased DOC se- cretion rate which was considered to be responsible for his hypertension.
Case Report
K. R. (UH 177-38), a 31-yr-old white male, was seen initially at the University Hospital in August 1961 because of hypertension and severe headaches, which were first noted in June 1960. Six months later he observed the development of tender gynecomastia bilater- ally. This was associated with a decrease in testicular size and consistency as well as in libido and sexual potentia.
On physical examination his blood pressure was 168/100. There was grade II hypertensive retinopathy with an A/V ratio of 1:3. Gyneco- mastia was present bilaterally, accompanied by increased areolar pigmentation and hyper- trophy of the glands of Montgomery. Both testes were scrotal, each measuring 2×3 cm. The remainder of the physical examination was within normal limits.
Routine laboratory studies, including serum electrolytes, were normal. A pentolamine test was negative and urinary vanillyl mandelic acid excretion was normal. A right adrenal mass was
FEMINIZING CARCINOMA
detected by intravenous pyelography. Retro- grade abdominal aortograms showed evidence of “multiple tortuous vascular channels” in the region of the tumor mass, with no evidence of right renal involvement.
The following endocrine studies were carried out prior to surgery: 1) Total biologically active estrogen excretion titers were increased to 11.5 ugEq estradiol benzoate/24 hr (normal adult male range 0.4-3.0 µgEq/24 hr). The method of Maddock was utilized (6). 2) Urinary 17-keto- genic steroid levels were 44.2 mg/24 hr [normal male range 8-25 mg/24 hr, method of Norym- berski et al. (7)]. 3) Urinary general gonado- trophins were undetectable utilizing the kaolin- acetone extraction procedure and the immature rat ovarian weight method of Albert (8) (nor- mal male range 1.7-3.8 mgEq UPM-13/24 hr).
Laparotomy was performed on 10/17/61. A firm, encapsulated tumor of the right adrenal gland measuring 6-7 cm diameter and weighing 92 g was removed. Microscopic examination showed aggregates of neoplastic cells with intra- vascular invasion consistent with a diagnosis of “adrenocortical carcinoma.” Mahesh and Herr- mann (9), using paper chromatography, ex- tracted the tumor tissue and established the presence of 1.85 µg 116-hydroxyestrone, 2.45 µg estrone and 0.06 ug estradiol/g of tumor tissue. Following surgery there was a rapid decrease in breast tenderness and improvement of his libido and sexual potentia to normal. Six months later, while still asymptomatic, his uri- nary estrogen titers were found to be normal (1.1 ugEq estradiol benzoate/24 hr). Urinary 17-ketogenic steroid levels at this time were 13.7 mg/24 hr (Table 1).
Chest x-rays remained normal until July 1963, when a solitary 15 mm circular density was noted in the left lung. Further pulmonary lesions were detected the following month. During this period, the patient again noted a decrease in testicular size and an increase in breast tenderness. Total urinary estrogen values remained normal despite the presence of these symptoms. Urinary 17-ketogenic and 17- ketosteroid excretion studies done at this time are listed in Table 1.
In view of the evidence of metastatic involve- ment, the patient was started on 10 g daily of o,p’-dichlorodiphenyl dichloroethane (o,p’- DDD) in August 1963. Maintenance oral hydrocortisone, 30 mg daily, was started after the fourth week of o,p’-DDD therapy although the patient exhibited no clinical or laboratory
| Date | 17- 17- KGS KS*(15) | Comments | |
|---|---|---|---|
| 10-4-61 | 44.2 | Surgery 10-17-61 | |
| 4-2-62 | 13.7 | ||
| 7-31-63 | 16.8 13.2 | ||
| 8-14-63 | 8.2 6.7 After 3 days dexametha- sone (8 mg/d) | ||
| 8-21-63 | 3.8 After 1 wk 10 g o,p'-DDD /d | ||
| 8-28-63 | 11.9 After 2 wk 10 g o,p'-DDD /d | ||
| 9-4-63 | 10.2 After 3 wk 10 g o,p'- DDD/d | ||
| 9-11-63 | 10.2 After 4 wk 10 g o,p'- DDD/d | ||
* Normal male range =8-20 mg/24 hr.
evidence of adrenal insufficiency. Because of toxic symptoms, the dosage of o,p’-DDD was reduced to 4.0 g daily, and finally discontinued in January 1964. There was no objective evi- dence of tumor progression by x-ray during the administration of the o,p’-DDD. After the medication was discontinued, however, there was definite increase in size of his pulmonary lesions as well as further breast tenderness. In consideration of these findings, the o,p’-DDD treatment was resumed in August 1964 at a dose of 6.0 g daily.
Despite this therapeutic program, hyper- tension and increasing headaches posed a con- tinuing problem. In January 1966 the regimen was changed to 1.0 mg dexamethasone daily; the o,p’-DDD and hydrocortisone were discon- tinued. The following month he was trans- ferred to the Clinical Study Center, San Fran- cisco General Hospital, for determination of adrenal corticosteroid secretion rates. The data obtained at that time are tabulated in Table 2.
The patient continued to deteriorate. His pulmonary metastases, apparently inhibited while he had received o,p’-DDD, now pro- gressed in spite of the resumption of such therapy. In August 1966 the o,p’-DDD was discontinued again because of systemic in- tolerance. Thereafter, hemoptysis, increasing dyspnea, gross hematuria and ascites devel- oped. A short course of intravenous mith- romycin failed to produce a remission and the patient died on February 15, 1967.
Post-mortem examination revealed evidence of recurrent right adrenal carcinoma with metastases to the right kidney, liver and lungs. There was extensive lymph node involvement above and below the diaphragm. The right renal vein showed tumor invasion and thrombus formation, with extension to the inferior vena cava.
3 UPM-1, general gonadotrophin standard sup- plied by Endocrine Study Section, NIAMD, NIH.
| Urine | Total Porter-Silber chromogens (16) | 13.7 mg/24 hr (normal 5-10 mg/24 hr) |
| THS (17) | 5.1 mg/24 hr (normal 0-1 mg/24 hr) | |
| Secretory rate (18, 19) | Cortisol | 11.2 mg/24 hr (normal 10-31) |
| Corticosterone | 1.4 mg/24 hr (normal 0.9-4.5) | |
| Aldosterone | 18 µg/24 hr (normal 60-180) | |
| DOC | 609 µg/24 hr (normal 50-180) |
Discussion
Study of mineralocorticoid excretion in previously reported cases of feminizing adrenocortical tumors has been infrequent. Urinary aldosterone has been measured in only two other cases (10, 11), only one of which had hypertension (10). Five previous cases of feminizing adrenal tumors have had increased urinary THS levels (2, 5, 11-13). In the case described by West, Kumagai, Simons, Dominguez and Ber- liner (5) both urinary estrogen and THS titers increased after administration of ACTH, with no change in tetrahydrocorti- sone excretion. Incubation studies also demonstrated impaired conversion of DOC to corticosterone, thereby leading the authors to conclude that their patient had a relative 110-hydroxylation block. West et al. believed that this resulted in an accumulation of DOC, with resulting hypertension. Unfortunately, no DOC or aldosterone secretory rates were deter- mined, and their observations were not confirmed. An increased DOC secretory rate is documented in the present case (Table 2). In view of the sustained hyper- tension, it would appear that the ability to secrete increased amounts of DOC was present in the primary tumor as well as in the metastases.
The combination of subnormal aldo- sterone secretory rate (18 ug/24 hr) and a markedly elevated DOC secretory rate (609 ug/24 hr) provides in vivo evidence of decreased 116-hydroxylation. Prior to sur- gery, urinary THS levels were probably elevated since urinary 17-ketogenic ste- roids were increased in the absence of clinical Cushing’s syndrome. Later studies established the presence of elevated THS
levels (Table 2). Since elevated THS levels are characteristically encountered in the hypertensive form of congenital adrenal hyperplasia, the documentation of similar findings in our patient further supports the existence of a block in 116-hydroxyla- tion. It is of interest that patients 45, 49 and 52 listed in Gabrilove’s review on feminizing adrenal tumors (1) also showed elevated THS associated with normal or decreased urinary THE and THF titers.
Survival rates in feminizing adreno- corticoid carcinoma are difficult to calcu- late due to the rarity of the syndrome, lack of adequate follow up, and confusion with respect to histology. Gabrilove, Sharma, Wotiz and Dorfman (1) found that 50% of patients died within 12 years after onset of symptoms, and 80% within three years after onset.
Data on blood pressure are available in only 37 of the patients reported, 32 of whom had carcinoma.4 When these latter patients are considered separately, there appears to be a better prognosis in those patients with hypertension as compared to those who were continuously normotensive. As shown in Tables 3 and 4, mean survival after surgery for those patients without hypertension was 24.8 months, as com- pared to 48.3 months for those with hyper- tension. Twelve additional patients are not included in Tables 3 and 4 due to inade- quate information provided in the original papers, follow-up periods of less than one year, or the existence of other postopera- tive complications not related to the tumor.
Since these patients underwent laparot-
4 In view of frequent ambiguity of histologic picture, we have accepted the tumor classification as listed by Gabrilove et al. (1).
FEMINIZING CARCINOMA
| Author | Age | B. P. | Duration (months) | |||
|---|---|---|---|---|---|---|
| Symptoms before surgery | Survival post surgery | |||||
| Myhre (20) | 62 | 135/95 | 72 (prior to detectable tumor mass) | 84* | ||
| Wallach et al. (21) | 120/60-160/100 | 160-200/100-120 | ||||
| (West et al.) (5) | 28 | (early) | (late) | 24 | 55.5 | |
| Dohan et al. (22, 1) | 30 | 140-200/100-135 | 72 | 48 | ||
| Kerr and Gordan (23) | 44 | 135/85-220/120 | 36 | 70 | ||
| Stewart et al. (24) | 26 | 140-165/80-110 | 12 | 5 | ||
| Gabrilove et al. (1) | 53 | 130/80-160/100 | 24 | >24+ | ||
| Dorner et al. (25, 1) | 54 | 160/80-185/115 | ? | >36 + | ||
| Present case | 31 | 170/110 | 12 | 64 | ||
* Duration from onset of symptoms (inoperable).
t Still alive at time of report.
omy only after the presence of gyneco- mastia suggested adrenal pathology, it appears unlikely that those patients with hypertension had a better prognosis be- cause of earlier discovery of symptoms. It is possible, however, that the ability of these tumors to produce a variety of steroids, especially of the 11-deoxy type, is inversely related to the degree of malig- nancy. Thus, the more malignant tumors would be less likely to be associated with either a prolonged survival or hypertension.
In contrast to the apparent sustained increase in mineralocorticoid secretion,
evidence of elevated estrogen titers was present only before removal of the pri- mary tumor. Subsequent estrogen values (0.5-1.1 ugEq estradiol benzoate/24 hr) were all within the normal range in spite of increasing metastases. Spencer et al. (14) have presented data documenting the differences in steroidal biosynthesis that may occur in the metastases as compared to the primary adrenal tumor. The failure of the gynecomastia to recur after the development of the pulmonary metas- tases is consistent with the urinary estro- gen values obtained, although the recur-
| Author | Age | B. P. | Duration (months) | |
|---|---|---|---|---|
| Symptoms before surgery | Survival post surgery | |||
| Lisser (26) | 33 | 112/88 | 1 month (prior to initial examination) | 2.0* |
| Simpson and Joll (27) | 34 | 116/70 | 18 (approximate) | 23 |
| Armstrong and Simpson (28) | 40 | 128/88 | 4 | 5 |
| Staubitz et al. (29) | 38 | 130/78 | 57 | >12} |
| Landau et al. (1, 30) | 28 | 120/80 | 192 (onset puberty) | 60 |
| Higgins et al. (31) | 26 | 140/80 | 9 | 6 |
| CPC, NEJM (32) | 66 | 128/64 | 12 | 24 |
| Huguenin et al. (33) | 39 | 140/90 | "several" | 5 |
| Ferrier et al. (34) | 43 | 110-120/ | 2 | 8 |
| Molnar et al. (2) | 34 | normal | ? | >42} |
| Decourt et al. (12) | 32 | 130/80 | 8-9 | 27 |
| Bacon and Lowrey (3) | 6 | 115/60 | 12 | 84 |
* Duration of survival from onset of symptoms (inoperable).
t Still alive at time of report.
rence of the breast tenderness is unex- plained.
The use of o,p’-DDD may have con- tributed to the prolonged survival in the present case. We were unable, however, to demonstrate any evidence of objective tumor regression with this drug during three years of treatment.
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