ADRENAL CORTICAL CARCINOMA IN A MALE WITH EXCESS GONADOTROPIN IN THE URINE
WALLACE L. CHAMBERS, M.D.
From the Philadelphia General Hospital, Philadelphia, Pennsylvania
T UMORS of the adrenal cortex with symptoms of hypercorticoidism are infrequent (1-3). Most of the cases reported presented masculini- zation (in females) or the adrenogenital syndrome (in males or females); a few showed evidence of feminization (in males) (4-12). Adrenal cortical tumors associated with excess gonadotropin seem to be exceedingly rare. A search through the literature revealed only one case (McFadzean) (13):
The 29-year-old patient was admitted because of unexplained fever. He gave a history of symptomless breast enlargement of eighteen months’ duration, of weight gain of one year’s duration, and of decreased sexual activity and libido of six months’ duration. A large tumor mass was palpable in the upper left quadrant. The breasts were well de- veloped, the genitalia were normal, and there was a slight feminine distribution of his hair. X-ray examination showed a soft tissue mass with displacement of the left kidney. The lungs were clear. Urinary estrogens or gonadotropins were not assayed, but a Fried- man test was positive. Twenty days after successful removal of the tumor, the Friedman test was found to be negative. Sexual interest and activity returned, and by the forty- third postoperative day the beard was thicker and periareolar hair had grown. The tumor was mostly encapsulated, multilobulated and weighed 1420 Gm. It showed fibrous cores, multiple hemorrhages and light gray areas, and one lobe resembled the “classical hypernephroma.” Microscopic examination revealed an adenocarcinoma, the structure resembling that of adrenal cortex with various types of nuclei and some vacuolization.
As only one case was found in the literature, it seemed of interest to re- port another case in which both Friedman tests and gonadotropin assays were made.
CASE REPORT
Present illness: The patient was a white male, 39 years old at the time of his first hospital admission July 31, 1947. The presenting complaints were cough with hemoptysis, hema- turia occurring at the end of micturition, bloody ejaculation and continuous progressive pain in the left arm and both flanks. These complaints had developed over the preceding ten or eleven weeks. Diagnosis of metastatic malignancy was made, although the primary site was not discovered. The patient received deep x-ray therapy (8 series, 200 r) before his discharge on August 22. At the time of the second hospital admission in September 1947, he stated that all symptoms had persisted and progressed in severity except the hematuria. In addition, the breasts had become sore. The flanks, which ached continu- ously were sore to the touch, and pain in the chest accompanied the productive cough. On being questioned, the patient stated that he had noted continuous right frontal headache and pain in the right eye, but no impairment of vision. Eight days prior to the
Received for publication September 1, 1948.
second admission, nausea and vomiting had occurred without pain or hematemesis. There had been recent constipation, but no hemorrhoids or melena. Marked weakness was re- ported.
Physical examination: The patient was a well developed, fairly well nourished, white man who appeared acutely ill. He had a paroxysmal cough productive of bloody sputum. Extreme tenderness and pain accompanied movement of all extremities, particularly the left shoulder and arm. Positive findings in the mouth and throat were dental caries and enlarged tonsils. On examination of the chest there was tenderness of the nipples but no enlargement of the breasts. Breath sounds were decreased bilaterally but there were no rales or alteration of fremitus. The heart was normal in size, the sounds were clear, and the rate was 100 with irregular rhythm. An abdominal mass the size of an orange was palpable in the right upper quadrant laterally, with tenderness present over the mass and tenderness in the left lower quadrant near the ileum. No other organs or masses were palpable. The genitalia were normal in size and appearance. No blood or discharge could be expressed from the urethra, but the prostate was slightly enlarged and soft. A large soft fixed lymph node was palpable in the left axilla. Except for absence of the left triceps, biceps and wrist jerks, the neurologic findings were normal.
X-ray and laboratory data: First admission (Mt. Sinai Hospital):1 An x-ray picture of the chest was interpreted as showing a metastatic malignant lesion. An intravenous urogram demonstrated ptosis and slight enlargement of the left kidney. No additional information was obtained from cystoscopic examination, urine examination for acid-fast organisms, x-ray examination of the left shoulder girdle, left arm and gall bladder, gastro-intestinal series and barium enema. Bronchoscopy in August 1947 was reported as showing “a com- pression of the right lateral and posterior walls of the mid-trachea by an external mass which cut the lumen by one-third. The overlying mucous membrane was normal; other- wise the bronchoscopic findings were normal.” Bronchial secretion was devoid of acid- fast organisms and malignant cells. The Friedman test was reported positive August 18, and the positive finding confirmed on a second test. Study of urinary hormone output on September 2 showed the patient was excreting 50,000 mouse units of Prolan A per 100 ml. of urine.
Second admission (Philadelphia General Hospital): X-ray examination of the chest showed metastatic malignancy throughout. Additional x-ray studies revealed early meta- static lesions of the lower left humerus and an enlarged right kidney, but no evidence of metastases to the skull, vertebrae or pelvic bones. An intravenous pyelogram demon- strated impaired function of the left kidney and a large irregularity suggesting primary malignancy. The right kidney functioned normally. Blood studies revealed 2.78 million erythrocytes and 10,850 leukocytes. There were 77 per cent polymorphonuclear cells, 21 per cent lymphocytes, 1 per cent monocytes and 1 per cent eosinophiles. Sugar was 81 mg. per cent, urea nitrogen 14 mg. per cent, and total protein 6.0 Gm. per 100 ml. with an A/G ratio of 3.4:2.6. The CO2 combining power was 17.6 mEq. and Cl (NaCl) 104.5 mEq. per liter. A Kline test was negative. Urinalysis showed a specific gravity ranging from 1.009 to 1.017. There was an occasional 1 plus albuminuria, and the sedi- ment showed 10 to 15 erythrocytes per high power field and many leukocytes.
Course: In spite of treatment by bed rest, opiates for relief of severe pain, and an in- dwelling catheter, the patient followed a rapidly declining course with gradual onset of severe dyspnea, and died October 16, 1947.
1 I am indebted to Dr. D. Meranze for letting me use these data.
Postmortem examination: The body was that of an extremely cachectic white male. The distal end of the left arm was diffusely swollen. The breasts were grossly normal. The serous membranes were all smooth and glistening and no adhesions or fluid were found. The vessels were normal throughout. There was no arteriosclerosis. The heart weighed 280 Gm. It was flabby and showed slight dilatation of the left ventricle and marked dilatation of the right ventricle. The left lung weighed 1300 Gm., the right 1800 Gm. External surfaces were smooth, blackened and nodular. Throughout the parenchyma of each lobe hard, purplish white nodules, measuring approximately 2 to 3 cm. in diameter, were found. The intervening lung tissue was congested. Bronchi and vessels were clear.
The spleen weighed 80 Gm. The capsule was smooth. The consistency was soft. The color was purplish. There was no evidence of tumor. The mesentery and mediastinal lymph nodes were enlarged and replaced by tumor tissue. The external nodes were normal. The left kidney weighed 330 Gm., the right 180 Gm. The entire lower pole of the left kidney was replaced by a tumor mass, measuring 8 cm. in diameter. It was round with an irregu- lar surface, and on cut surface was white in color with streaks of purplish red. In the mid- portion of the left upper lobe, a firm, round nodule measuring approximately 2 cm. in diameter was found. It was purplish-red in color but did not show as much firm, white tissue as the one in the lower lobe. The remaining parenchyma was pale and somewhat cloudy. The right kidney contained several small purplish nodules measuring from 1 to 2 cm. in diameter. Renal pelves were normal except for distortion by tumor masses. The ureters were normal. The urinary bladder was not changed. Both testes were normal in size and consistency. The prostate was normal. The esophagus, stomach and bowel were not changed. The mesentery of the small bowel contained small metastatic nodules ap- proximately 1 cm. in diameter, which were of the same consistency as the tumor tissue elsewhere. The liver weighed 2330 Gm. The interior and lateral portions of the right lobe
contained a tumor mass approximately 12 cm. in diameter causing extension of this lobe down to the iliac crest. There was a small metastatic nodule near the diaphragmatic por- tion and several very small nodules throughout the inferior portion of the left lobe. The latter nodules were purplish in color, while the large mass in the right lobe was white. The remaining liver substance was pale brown and somewhat greasy. The portal venous system was normal. Gall bladder and bile ducts were normal. The pancreas contained several small tumor nodules within the body, each approximately 1 cm. in diameter. The duct appeared to be normal. The left adrenal appeared to be normal. The right was changed into a round, firm, well encapsulated mass measuring 3 cm. in diameter. On cut section, it was homogeneously purplish in color and distinctly firm throughout. The thyroid appeared to be normal. The distal end of the left humerus was completely sur-
rounded by tumor tissue, similar to that described above. It was approximately 1 to 12 cm. thick in all areas around the distal end of the bone and appeared to replace the . periosteum. The underlying bone was rough and irregular. The tendon of the triceps brachii was completely replaced by this mass in its distal portion. The humerus was free below the condyles and below the mid-portion. On section, the tumor did not invade the bone at all, although the medullary substance was soft and of purple color. The remain- ing bones appeared to be normal. Brain and pituitary were not examined.
Microscopic examination: In some places, such as the lungs (Fig. 1), the tumor formed solid sheets of large polygonal cells with large somewhat vesicular nuclei not unlike the cells of the adrenal cortex. There were occasional giant cells with large hyperchromatic nuclei. There were many mitotic figures. In other places, such as in the liver (Fig. 2), the tumor formed bizarrely shaped spaces often lined with large endothelial-like epithelial
cells resembling chorion epithelium. The latter formed multinucleated giant cells in places. The small spaces surrounded by these cells contained protoplasmic debris and plasma, while the large ones contained erythrocytes and leukocytes as well. These por- tions of the tumors, too, contained abundant mitotic figures. All tumors showed more or less extensive necrosis. The one in the right adrenal gland was almost completely necrotic. There was little fat in the tumor cells except in the areas where they underwent necrosis.
The testes were somewhat atrophic. Spermatogenesis was almost completely sup- pressed. The spleen showed chronic splenitis with a good many plasma cells and ecsino- philes. The lungs, liver and kidneys were markedly congested, and there was extensive central necrosis of the liver lobules.
The final diagnosis was carcinoma of the cortex of the right adrenal with metastases to lymph nodes, lungs, liver, kidneys, pancreas and left arm. Cause of death was repira- tory and circulatory failure.
COMMENT
The case of adrenal cortical carcinoma reported here resembled that of McFadzean’s (13) in that the patient was a male, and excess gonadotropin was excreted in the urine; it differed in that it showed no convincing evi- dence of feminization. In the case of a male reported by Simpson and Joll (11) endocrine assays revealed excess estrogen excretion in the urine, but the Aschheim-Zondek test was negative, and no gonadotropin was demon- strable. These observations seem to show that adrenal cortical carcinomas may be associated with either excess estrogen excretion or excess gonado- tropin excretion or both.
The cellular sources of gonadotropins are generally believed to be the chorion epithelium of the placenta and the anterior lobe cells of the pitui- tary gland. In the case reported here, as in McFadzean’s case, we have no evidence that the gonadotropins were produced by either placental tissue or the pituitary gland. In our case, the histologic structure of the tumor resembled that of adrenal cortex in most places, though here and there the cells showed differentiation towards elements resembling chorion epi- thelium (Fig. 2). In McFadzean’s case, the Friedman test became nega- tive promptly after successful removal of the tumor; whereas in cases with excess hypophyseal gonadotropin excretion secondary, for instance, to seminoma testis, successful treatment of the tumor is said not to cause a prompt fall in gonadotropin and the hormone continues to be excreted in the urine in excessive amounts for some time (13). Moreover, McCullagh and Cuyler(14) reported a case of Cushing’s syndrome due to a pituitary adenoma in a woman with a positive reaction to the Friedman test. Her symptoms and the gonadotropin excretion all disappeared following de- nervation of both adrenals and right hemiadrenalectomy, without therapy to the pituitary gland. These observations seem to indicate that the ad- renals may be instrumental in the elaboration of gonadotropic hormones.
SUMMARY
A case of adrenal cortical carcinoma in a man with excess gonadotropin excretion is reported. The patient excreted 50,000 mouse units of gonado- tropin per 100 ml. of urine and the Friedman test was positive.
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