Adrenocortical Carcinoma with Ectopic LH Production
Helmut Gadner, Bruno Weber, and Hansjörg Riehm Kinderklinik der Freien Universität Berlin
Received March 21, 1974
Abstract. This report concerns a 31/4-year-old boy, in whom a left-sided adreno- cortical adenocarcinoma of predominantly androgenic potency caused isosexual precocious development with enlargement of the testicles and, probably, predomi- nantly testicular testosterone secretion. It was possible to identify an increase in LH production as the cause of this phenomenon; the seat of origin was the tumor. Ectopic LH production was proved upon extraction of the tumor and by the decline of gonadotropic activity after its removal.
Key words: Adrenocortical carcinoma — Testosterone - Ectopic LH production - Precocious androgenization.
Most tumors of the adrenal cortex in childhood are carcinomas (Hayles et al., 1966). They may occur at any age, and their incidence has been stated to be 2 cases per 1 million of the overall population (Hutter and Kayhoe, 1966a). According to a mortality rate due to cancer of 71.47 per million per year in children under 15 years of age, the rate of death from adrenocortical carcinoma is 0.06 (Miller, 1969). This implies that about 2 out of 1000 children with fatal neoplastic disease may die annually from this tumor (excluding leukemias and lymphomas with an overall mortality rate of 50%). The number of children afflicted with adrenal cortical carcinomas may be more than twice as high.
The most frequent leading symptom in adrenocortical carcinomas is that of more or less pronounced virilization (Burrington and Stephens, 1969; Hutter and Kayhoe, 1966a; Kenny et al., 1968); this is more con- spicuous in children than adults, and is often associated with hyper- cortisolism (Eberlein and Winter, 1969). An isolated Cushing syndrome, isolated feminization, and the simultaneous occurrence of virilization and feminization have been observed less frequently (Bacon and Lowrey, 1965; Eberlein and Winter, 1969; Fontaine et al., 1970; Halmi and Laskari, 1971; Hutter and Kayhoe, 1966a, b). Occasionally, hyper- aldosteronism or hypoglycemia have been reported (Eymontt et al., 1965; Scholz et al., 1967). Hormonally inactive carcinomas occur only in
adulthood, in which they account for the majority of all malignant adrenal tumors (Huvos et al., 1970). Adrenocortical carcinomas are-simi- lar to the Wilms’ tumor and primary carcinomas of the liver-more frequently associated with congenital hemihypertrophy, tumors and anomalies of the brain, abnormalities of the urinary tract, contralateral adrenal gland agenesia and hamartomas (Fraumeni and Miller, 1967; Haicken et al., 1973; Miller et al., 1964). The literature indicates a prefer- ence of adrenocortical carcinomas for the feminine sex (Bierich, 1967; Eberlein and Winter, 1969; Huvos et al., 1970; Labhart, 1971). On the other hand, several mortality statistics demonstrate a definite prevalence in males (Hutter and Kayhoe, 1966a, b).
The following is a report on a boy, now 7 years old, with an adeno- carcinoma of the adrenal cortex, in whom ectopic LH production of the tumor tissue together with excessive androgene production had resulted in an enlargement of the testicles, as well as symptoms of precocious androgenization. Except for 5 cases of feminizing adrenocortical carcino- mas featuring increased hypophyseal gonadotropin secretion (Rose et al., 1968), there are to our knowledge only four reports of probable auto- chtonic chorionic gonadotropin production in adrenocortical carcinomas. In 3 cases (Chambers, 1949; McFadzean, 1946; Rose et al., 1968) the subjects were adult males, the fourth case report concerned a 13-year- old boy (Zurbrügg and Wagner, 1970). We have no knowledge of any other adrenocortical tumors with “chorionic-like” LH production in childhood. Therefore, we feel justified in giving a detailed description of this case.
Case Report
Olaf K., born April 22, 1967, No. 1391|70
During a holiday in Denmark in June 1970, the boy, who was then aged 31/4 years, was admitted to a Danish hospital with unusually severe pains in the left side of the epigastrium, following a fall on a sandy beach. A painful abdominal tumor on the left was discovered, together with enlargement of the genitals and premature growth of pubic hair. The 17-ketosteroid (17-KS) excretion in the urine was con- spicuously high (32.2 mg/d, of which 56% = 18.1 mg was dehydroepiandosterone, DHA). Rapid growth (approximately 6 cm) had been observed in the boy during the foregoing 6 months. His mother had also noticed an enlargement of the penis with an accompanying tendency towards erection, together with the development of a downy growth of pubic hair. For family reasons the boy was transferred to Berlin for further diagnosis, an adrenocortical tumor being suspected. No knowledge was obtained of any untoward incidence of tumors within the patient’s family.
With a height of 105 cm (mean for age: 97 cm) and a weight of 16.5 kg (normal weight for his height: 17.1 kg), the boy was sturdily developed, and gave a healthy impression. No hemihypertrophy or congenital malformations were noted. Deep in the left side of the epigastrium, a tumor of uncertain delineation, but no longer painful under pressure, could be detected by palpation. The penis was enlarged
?
(7 cm long), likewise both testes, which were measured at 3 ml. At the root of the penis and on the mons pubis numerous, crinkly pubic hair was noted (stage III according to Tanner). No axillary hair or signs of acne were present, and the voice was infantile. Corresponding to the general acceleration (height age 41/4 years), the skeletal age was found to be 6 years (chronological age: 31/4 years). Clinical findings were otherwise normal. Infusion urogram revealed an expanding process in the region of the left upper renal pole. With the aid of an abdominal aortography, this was defined as a tumor about the size of an apple situated cranially from the left kidney and probably retroperitoneal, with atypical blood vessels, causing dis- placement of the spleen and stomach (Fig. 1). In conjunction with the greatly accelerated erythrocyte sedimentation rate (64/98 mm), the findings were strongly indicative of a malignant process. There were no signs of metastases (chest X-ray and EEG normal). The blood pressure was within normal limits (100/70 mm Hg- 8 cm cuff); blood count, urinalysis, blood sugar, and electrolyte values in the serum were regular. The 17-KS excretion (17.2 mg/d with the method according to Few) was clearly above normal; following ACTH stimulation (25 IU = 1 mg Synacthen®
5 Z. Kinderheilk., Bd. 118
i.m.), no further increase occurred. The slightly increased 17-hydroxycorticosteroid (17-OHCS) excretion (8.4 mg/d) was raised by ACTH to 19.5 mg/d. In view of the almost certain tumor diagnosis following aortography, it was deemed advisable not to carry out a dexamethasone suppression test, as this would have delayed the surgical removal of the tumor. Using a biological method, the gonadotropin ex- cretion in the urine was barely measurable (4 MU-units/d). The plasma LH con- centration (14 and 15 mIU/ml respectively, radioimmunoassay) was elevated to adult levels. The plasma testosterone was likewise found to be excessively high for the boy’s age, at 850 ng/100 ml plasma (normal figures for this method, without plasma extraction: 4 to 75 ng/100 ml, radioimmunoassay; Hasan et al., 1973). In contrast, the estrogen excretion was only slightly above normal (3.5 ug/d).
Laparotomy was performed on 6 July 1970. A retroperitoneal tumor of the left adrenal cortex as large as a good-sized apple (70 × 60× 40mm) was found, surrounding the renal vessels and infiltrating into both the splenic capsule and the retroperitoneal cavity. The tumor and the left kidney were removed in toto, together with para- aortic lymph nodes. Macroscopic examination revealed a central hemorrhage within the tumor, which was probably attributable to the minor trauma the boy suffered before. Part of the tumor was immediately deep-frozen in carbon dioxide snow for further investigation. Microscopic examination revealed a solid carcinoma of the adrenal cortex without penetration into the kidney. Besides the polygonal, epithelial cells located in the slender, densely packed cords and nests, extensive necrosis, some confluent, were found together with fresh and older hemorrhages. There were no metastases in the adjoining lymph nodes. Extraction of the tumor tissue revealed large quantities of LH (30 IU/mg solid tissue, corresponding to about 740 IU/g tumor weight, method according to Karg and Parlow). Postoperative treatment consisted of radiotherapy with Tele-cobalt60 over an area of 14 x 7 cm on the left side of the abdomen, amounting to a total tissue dose of 4000 rads. Chemotherapy with cyclophosphamide (20 mg/kg body weight i.v. at 14-day intervals) was started at laparotomy, and concluded after 6 months (total dose 3400 mg = 20 mg/kg body weight, the average weight being 15.4 kg). Apart from some untoward reactions to radiation treatment and chemotherapy, the postoperative course was uneventful. However, 24 days after the removal of the tumor, another laparotomy was neces- sary because of an adhesion in the region of the duodeno-jejunal flexure which caused an ileus with vomiting and hypochloraemic alkalosis. After a rapid recovery, the boy was discharged and subsequently kept under ambulatory control. Post- operatively, the size of the testicles diminished (1 ml in August 1971) and the penis shrank from 7.0 to 5.5 cm in October 1971. The pubic hair disappeared by October 1971, and no further erections were observed after February 1972. The rate of growth also decelerated (from 6 cm in the last half year before the operation to 7 cm in the first year thereafter), while the maturation of the skeleton seemed to have slowed down definitely. The 17-KS and 17-OHCS excretion as well as the LH plasma concentration (3 mIU/ml) had already reverted to normal shortly after removal of the tumor (Fig. 2). The testosterone level fell to normal values (17.1 and 14.5 ng/100 ml, respectively) (Fig. 3).
As of March 1974 (33/4 years after diagnosis), neither local recurrence nor metastases have been observed (chest X-ray, EEG, and neurological status normal). The skeletal age corresponded to that of a 7-year-old child. The boy measured 121.3 cm (mean for age: 123 cm). His physical ability was completely normal. The length of his penis was then 5.2 cm, both testicles were of normal size (2 ml). There were no indications of pubertal development (no pubes, no axillary hair, no acne, infantile voice). LH and testosterone values in the blood and 17-KS, 17-OHCS and estrogen excretion in the urine corresponded to the boy’s age.
URINARY 17-KETOSTEROIDS mg/24h
20
ACTH 25 IU i.m.
ADRENALECTOMY
16
12
8-
4
0
0
1
YEARS
2
3
4
ADRENALECTOMY
800
TESTOSTERONE ng/100 ml
700
PLASMA
600
500
100
0
0
1
YEARS
2
3
4
Discussion
Virilization with macrogenitosomia, growth of pubic hair, and rapid acceleration of the growth rate without high blood pressure or signs of Cushing’s syndrome in this 31/4-year-old boy indicated an increased androgen production, the cause of which was ascertained by simple clinical means (palpation, urogram) to be a left-sided adrenocortical tumor. The tumor proved to be an adenocarcinoma with local invasion but no remote metastases. The expected increase of the 17-KS excretion 5*
was predominantly (56%) at the expense of DHA, corresponding to other case reports in literature (Bierich, 1967; Cooke, 1968; Eberlein and Win- ter, 1969; Yamaji and Ibayashi, 1969; Labhart, 1971). However, this weak androgen (Bierich, 1967; Cooke, 1968) could not be regarded as solely responsible for the intensive and rapid virilization of the boy, as evidence of large concentration of testosterone in the plasma was found. In contrast to the average value for pre-puberal boys (30 ng/100 ml), the plasma concentration in this case was 30 times as high (850 ng/100 ml). This testosterone increase can hardly be explained solely by the peri- pheral metabolization of the DHA produced in the tumor, especially since the 17-KS excretion could not be considered excessive. In addition, other metabolites of DHA, such as estrogens, were only increased slightly (3.5 ug/d). It must be assumed, therefore, that the production of testo- sterone was increased per se. If, however, the tumor had been the only source of this testosterone, there would be no explanation for the increase in LH values both in the urine and in the plasma, as indeed an increase of testosterone would have caused an inhibition of the pituitary LH secretion via the physiological feedback mechanism. On the other hand, the assumption of an increased testosterone production in the tumor alone would not offer a plausible explanation for the enlargement of the testicles, which indicated a gonadotropin-dependent isosexual precocious puberty rather than a mere androgenization. Only the existence of an additional ectopic LH production, which is not subject to physiological regulation, succeeds in synchronizing the otherwise conflicting symptoms : hormonally active adrenocortical carcinoma, enlargement of the testicles, simultaneous increase of LH and testosterone plasma values. The ex- traction of LH from the tumor and the drop in LH plasma concentration following removal of the tumor constitute circumstantial evidence for this assumption. The increase of testosterone could then be interpreted as a function of the Leydig cells in the testicles, and would not necessarily be derived from the tumor. Unfortunately, this hypothesis cannot be proved, as no biopsy of the testicles was undertaken. Neither could any studies of the biosynthetic properties of the tumor tissue be carried out. Nevertheless, this interpretation is the most plausible. This assumption also offers an explanation for the postoperative drop in the testosterone plasma concentration, which then would be at least partly due to the sudden interruption of the LH secretion. The reduction in size of the testicles is presumably attributable to the same cause. The excessive secretion of testosterone and the altogether comparatively slight enlarge- ment of the testicles to about 3 ml are not contradictory, as LH extracted from the tumor is only capable to stimulate the Leydig cells, while FSH is responsible for the growth of the tubular tissue, and thus for the enlargement of the testicles. FSH, however, was not found in the tumor.
Other tumors with ectopic LH production also secrete mainly LH and comparatively little FSH (Faiman et al., 1967; Liddle et al., 1969; Omenn, 1971; Wyss et al., 1971). Of course, stimulation of the gonadal function under such circumstances can only be incomplete.
Epicritically, therefore, the boy’s malignant tumor had both andro- genic and gonadotropic potency. Normal blood pressure, inconspicuous electrolyte concentration in the serum and only a slightly increased excretion of 17-OHCS seem to exclude any considerable glucocorticoid and mineralocorticoid activity of the tumor. The preoperative response of the adrenal cortex to ACTH was also normal, thus more or less pre- cluding any atrophy of the normal adrenal parenchyma, which is subject to regulation. This rendered postoperative cortisone substitution unneces- sary. The ectopic LH production brought about a genuine sexual pre- cocity, and not a pseudo-pubertas praecox, as should be expected in adrenocortical tumors with an isolated androgen production.
The authors are grateful to Prof. Hammerstein and Dr. Römmler, Department of Gynaecological Endocrinology, Klinikum Berlin-Steglitz, for performing the urinary gonadotropin and estrogen determinations and for measurements of plasma LH concentration, and to Dr. Hasan, Department of Endocrinology, Schering AG Berlin, for determination of plasma testosterone levels. In addition, they would like to thank Prof. Bettendorf, Department of Gynaecological Endocrinology, University of Hamburg, for the hormone extraction from the tumor tissue.
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Dr. Helmut Gadner Kinderklinik der Freien Universität D-1000 Berlin 19, Heubnerweg 6