NONHORMONAL ADRENAL CORTICAL CARCINOMA: REPORT OF CASE WITH 5 YEAR SURVIVAL AND RELIEF OF HYPERTENSION
ZACHARY R. COTTLER
From the Department of Urology, Jewish Hospital, Brooklyn, N. Y.
A survey of the recent literature on tumors of the adrenal cortex reveals a de- cided emphasis on hormone-producing neoplasms. This can be readily under- stood for the following reasons: 1) the striking changes that these tumors evoke in the external configuration of the human body; and 2) the equally dramatic changes that take place following their successful extirpation. On the other hand, the paucity of reports of nonhormone-producing tumors can be ascribed to: 1) their rarity, a comparative incidence not having been established as yet; 2) the absence of early symptomatology; and 3) the possibility that, in the late stages of the disease with metastases, confusion may arise as to the origin of the primary growth for the adrenal is often the site of metastatic deposits from car- cinomata of other organs.
The nonhormonal type of adrenal malignancy is usually discovered in its late stages when it becomes manifest by the presence of a definitely palpable mass, vague abdominal and flank pains, malaise, diminution of appetite, and, like a silent hypernephroma, by signs and syptoms due to a metastasis in the lung or some other organ. The duration of symptoms ranges from 8 months to 2 years with an average of 1 year. These neoplasms are seen practically only in adults over 30 years of age and without predilection for either sex (Cahill, Hartung, Macera, Stevens, Gibson, Loeb, etc.).
The diagnosis of adrenal cortex disturbances has been greatly facilitated by the recent advances in endocrinology, 17-ketosteroid urinary excretion studies, and the studies in electrolyte and vitamin C balances (Beall, Beall and Reichstein, Grollman, Soffer, Szent-Gyorgi, etc.). Of greatest aid, especially in hormonal tumors, has been the introduction of perirenal insufflation of air by Carelli, and its popularization and simplification by Cahill and Mencher. This procedure, in conjunction with excretory urography and laminography, is of inestimable value in the diagnosis and localization of diseases and neoplasms of the retroperi- toneal organs.
Thus far, the treatment of nonhormonal malignancies has been surgical extir- pation, when possible, followed by high voltage irradiation to the operative site and to metastases, as they arise. Three operative approaches have been used for adrenal tumors: 1) extraperitoneally, through a lumbar incision; 2) transtho- racic; and 3) transperitoneal. Cahill prefers the last, claiming it affords the best exposure and permits of ligation of the pedicle before the tumor is manipulated. Young and Crile preferred the lumbar route, and Broster, the transthoracic.
The prognosis of the nonhormonal neoplasms is poor because they attain large size and often metastasize before presenting any symptoms. Of Cahill’s 4 cases, reported in 1942, one died 11 months after operation; one was admitted in a mori-
bund state with widespread metastases; one had a metastatic tumor, 2 years after operation, involving the aortic glands and inferior vena cava, but died 6 months later of peritonitis due to perforation of a sigmoid diverticulum; and the fourth was but 2 months postoperative. Roome’s patient died shortly after op- eration. Loeb’s patient was presented in 1941, 2 and } years after operation with metastases present. Gibson’s case died postoperatively after an unsuccess- ful attempt to extirpate the mass, and at autopsy pulmonary metastases were found. Stevens’ patient died 8 weeks after operation with metastases in the liver and lungs. This patient is the youngest, a 17 year old male with a 22 month history. The tumor, however, was not a clear-cut nonhormonal type for he pre- sented certain features, such as pigmentation, usually associated with the hor- monal type of neoplasm. Timoney’s patient had an enormous nonmalignant adenoma.
It is not within the scope of this presentation to discuss etiology, physiology, pathology, etc. of these neoplasms. Their features are ably set forth in the paper of Cahill, Melicow and Darby, and in the monographs of Grollman and Soffer. We wish to present a case of nonhormonal carcinoma of the adrenal cortex in which metastases were discovered about 2} years after surgical extirpation and the patient is still alive and comfortable 5 years after the procedure. The patient also presented a marked hypertensive state which was permanently alle- viated after removal of the neoplasm and homolateral kidney.
CASE REPORT
B. G., Jewish Hospital of Brooklyn, No. 254352, a 50 year old Russian Jewess, was admitted to the gynecological service on May 26, 1942 with the chief com- plaint of “falling of the womb.” This condition had been present for several years. In addition, she also had episodes of rectal bleeding and tenesmus. There was no history of urinary disturbance. She was a gravida 9, para 3, and her last mentrual period occurred 1} years ago. The rest of her past and fa- milial histories was essentially negative.
Abdominal palpation revealed the presence of a large, hard mass that filled the entire right side and flank. It extended from underneath the costal margin to a short distance below the iliac crest. The liver seemed separate from and anterior to this mass. The liver edge was palpable 10 cm. below the costal border. The mass moved but slightly with respiration. Vaginal examination disclosed a re- laxed introitus, a large rectocele, and a smooth, atrophic cervix. The uterus was small and the adnexae normal. There was no cervical, submaxillary, axil- lary or inguinal lymphadenopathy. Temperature was 99.8 F, pulse 88 and res- pirations 24. The blood pressure was 290/170 and ranged between 250/140 to 264/116 to 190/122 to 184/154 to 178/140 during the preoperative period.
Laboratory examinations: Urine alkaline, specific gravity 1013, albumin 2 plus, glucose 0, microscopically negative, culture negative. Hemoglobin 74 per cent, erythrocytes 3,680,000, leucocytes 6,500, polymorphonuclears 68 per cent, bands 5 per cent, lymphocytes 25 per cent, monocytes 2 per cent. The Kline test was negative. The sedimentation rate was 63 mm. in 1 hour. Blood chemistry:
Sugar 91, urea nitrogen 19.2, phosphorus 4.2 and sodium 306 mg. per 100 cc. An electrocardiogram showed a sinus tachycardia and left axis deviation.
An x-ray showed the presence of a large mass in the right upper quadrant. Excretory urography revealed the pelvis and calyces of the right kidney to be depressed and deformed with the pelvis at the level of the fourth and fifth lumbar vertebrae. Left urinary tract was normal in appearance. There was a calcific shadow just to the left of the midline between the left eleventh and twelfth ribs (fig. 1, A). A barium enema showed evidence of extrinsic pressure on the hepatic flexure and right half of the transverse colon.
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Cystoscopy on June 5, 1942 showed mild cystitis and trigonitis. Indigo car- mine retruned in 5 minutes in 4 plus concentration from both sides. A 5F ureteral catheter was passed up the right ureter but met an obstruction at 19 cm., although a flow of clear urine was obtained. A retrograde pyelogram was made with 48 per cent hippuran solution. This confirmed the excretory urogram, and a lateral projection showed the pelvis to be displaced far anteriorly (fig. 1, B). The calcific shadow was visualised in the anterior abdomen and believed to be a gall stone in a displaced gallbladder.
The preoperative diagnosis was right renal neoplasm. On June 6, 1942, with the patient under nitrous oxide-ether-oxygen anesthesia, through a curved right loin incision, 25 cm. long, a very large, firm mass was found within Gerota’s fascia. Numerous dilated veins, ranging up to 1 cm. in diameter, coursed over
its surface. The twelfth rib was cut but not removed. The upper pole of the tumor was markedly adherent to the diaphragm, and, in freeing it a rent was made in the pleura. This was immediately repaired and protected by packing. Another opening was inadvertently made in the peritoneum, through which the liver was explored and found to be free of metastases. The gallbladder, which with the right lobe of the liver had been displaced anteriorly and to the left by the mass, was found to contain a large calculus. This accounted for the calcific shadow seen to the left of the midline on the radiographs. The peritoneal rent was repaired after the anterior surface of the mass had been freed. After de- livery of the upper pole of the mass, the kidney was exposed, attached to the mass and lying anteriorly to it. The kidney was also rotated on its transverse axis. The patient’s condition became grave, and rather than tediously dissect the neoplasm from the kidney, it was deemed best to do a nephrectomy. The mass
and the kidney were removed in toto. The postoperative diagnosis was adrenal neoplasm.
Pathological report (Dr. D. M. Grayzel): The right kidney measured 11 by 6 by 2.5 cm. and weighed 152 gm. The attached mass measured 23 by 12.2 by 8 cm. It did not involve the renal parenchyma. The external surface was lobu- lated and was red-grey and brown in color. The consistency was mostly firm, but soft and cystic in areas. Stretched over the surface, in one area, was a band of bright yellow-brown tissue 14 cm. in length. This merged indistinctly with the tumor mass. On section, a variegated appearance was presented. Most of the tumor consisted of grey-brown elastic tissue arranged in a lobulated fashion. The central portion was composed of gelatinous yellow-grey material as well as irregular cysts measuring up to 4 cm. in diameter and filled with muddy red- brown material and friable, soft, grey-green tissue. In some places, areas of hem- orrhage, up to 3 cm. in diameter, were seen (fig. 2).
Microscopic examination: In some areas, the cells appeared to be mounted in many rows, on delicate connective tissue stalks with vascular cores. In other areas, the cells were in nests and sheets enclosed by delicate bands of collagenous
tissue. In still other areas, the cells tended to arrange themselves about irregu- lar lumina. The cells were large with marked variation in size and shape. The cell outlines were distinct, the cytoplasm abundant, granular, or foamy, and occasionally clear. The nuclei, in many, were round or oval, and vesicular with prominent nucleoli. In others, the nuclei were hyperchromatic and bizarre- shaped. Some were in mitotic division. Giant tumor cells were also seen in scattered areas. There were many engorged capillaries and venules containing tumor cells. In other preparations, the tumor cells were seen about nerve bundles. In one preparation, bordering the tumor and well demarcated from it by a connective tissue capsule, there was a narrow band of adrenal gland tissue,
which showed both cortical and medullary zones. The cells appeared well pre- served. Preparations from the kidney showed nothing of note. Diagnosis: Adenocarcinoma of the adrenal gland (fig. 3).
Convalescence was somewhat stormy. The patient received desoxycortico- sterone acetate, glucose and saline infusions, blood and sulfadiazine. Right basal pneumonitis developed. The temperature ranged about 101º F during the first week and then gradually subsided. She was discharged on the thirtieth day after operation. Urinary hormone studies on the fifteenth day showed the following: Prolan, negative; estrin, 14 rat units; androgen, 2.8 mg. in 24 hours; all within normal range. Her blood pressure, postoperatively, ranged from 130/100 to 170/80 to 140/100 to 160/84 to 124/90 to 154/98 to 124/80 to 136/76.
The month following operation, the author entered the armed services and, upon resuming his civilian status 44 months later, was most pleasantly surprised
to find the patient alive and apparently in good health. She had received a course of radiation therapy to the operative site and abdomen, starting on July 28, 1942, consisting of 2500 r to each of 4 fields for a total of 10,000 r. On Janu- ary 19, 1943, a chest radiograph was negative for metastases. On March 26, 1945, 33 months after operation, a mass was felt in the right midabdomen, the size of a fetal head. Another course of therapy was administered of 200 r daily to two alternate fields for a total of 4000 r. On May 21, 1945, the mass was found to have maintained its size and the last course of therapy was repeated. The conclusion of this treatment found no diminution in size of the metastasis but the patient had lost 18 pounds in weight. Examination on September 14, 1945 re-
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vealed the presence of a large mass filling the left upper quadrant and the first mid-abdominal mass now had a companion to its left. Radiation therapy was now started to each of 8 portals, 4 anterior and 4 posterior, in daily dosage of 200 r to a total of 1600 r to each field. On October 4, 1945, 39 months after operation, x-ray of the chest revealed, for the first time, a right superior mediastinal para- aortic mass 8 by 4 cm. in diameter (fig. 4, A). On February 18, 1946 treatment was started to anterior and posterior chest portals in doses of 150 r to a total of 1500 r per portal. An excretory urogram, on December 24, 1945, revealed nor- mal function of the left urinary tract and without any deformity of the pelvis and calyces.
The patient’s general condition was good and she continued doing her own housework. She was comfortable despite the presence of the metastases. On September 30, 1946 she was re-admitted to the hospital. Her blood pressure
ranged from 150/90 to 114/64, averaging 120/80. An excretory urography re- vealed considerable displacement of the left renal pelvis by an extrarenal mass (fig. 4, B). The urea nitrogen was 19.2 mg, per cent. The phenolsulphon- phthalein excretion was 65 per cent in 2 hours. Hormonal assays, androgen and estrogen, were within normal range for a female of her age. The potassium tolerance showed a failure of a rise in blood level, a finding associated with adrenal cortical neoplasms.
At the present date, 5 years of observation postoperatively have been con- cluded. Her general condition can be considered good for she is fairly comfort- able, ambulatory, continues her household duties and requires no analgesics nor sedatives. Her blood pressure continues at a level of 120/80. There is no dimi- nution in the size of the metastases, but no others have appeared either clinically or radiologically.
DISCUSSION
This case is illustrative of the insidious onset and progression of nonhormonal adrenal cortical carcinomas. Had not the patient entered the hospital seeking surgical relief for a rectocele, the presence of the neoplasm might not have been ascertained until after metastases had appeared. This is a vivid example of the desirability of regular, thorough physical examinations if our campaign against cancer is to be effective.
The correct preoperative diagnosis of an adrenal neoplasm should have been made, had we considered its possibility and employed perirenal air insufflation. The presence of the enormous mass, the pyelographic deformity, and, as stated in our introductory remarks, the absence of the dramatic changes associated with the hormonal type of adrenal tumor, influenced us to consider this as a renal neoplasm. We have now become adrenal-conscious and have performed peri- renal insufflation frequently and successfully since then.
There are 2 remarkable features in this case. One is the attainment of a 5 year survival period despite the presence of extensive abdominal and mediastinal metastases. The patient is comfortable and it is possible that she may continue so for several more years before deterioration or spread to some vital center takes place. We have found no report of a similar survival. The effectiveness of the radiation therapy cannot be fully evaluated for these neoplasms are classified as being radio-resistant. Furthermore, the metastatic deposits apparently did not respond by receding or even slightly diminishing in size.
The second remarkable feature is the reduction of the severe preoperative hypertension to normal levels and the maintenance of this reduction over a 5 year period of observation. We believe that the hypertension was caused by torsion of the renal pedicle due to the depression and rotation of the kidney by the tumor. This probably caused a partial ischemia of the kidney as observed in Goldblatt’s phenomenon. As Selye has demonstrated experimentally, interference with the vascular supply of one kidney, where its mate is normal, causes the formation of pressor substances with a resulting hypertension which can be relieved by re- moving the diseased organ. An adrenal hormonal etiology for the hypertension
in this patient can be eliminated by reason of the persistence of the postoperative reduction to normal levels despite the presence of extensive metastases. Thus, to the slowly growing list of cured cases, observed for 5 years, of hypertension caused by unilateral renal disease, we add one caused indirectly by torsion of the renal pedicle due to the pressure of a very large adrenal neoplasm. What might have been the effect upon the hypertension had we but removed the mass and preserved the kidney is highly speculative. Now, that a metastatic mass in the left renal area is causing marked distortion of the left kidney, it will be extremely interest- ing to note what effect this will have on the blood pressure in the future.
SUMMARY
A case of nonhormonal adrenal cortical carcinoma is presented in detail because of some very interesting clinical features. The patient has attained 5 years sur- vival in comfort, although extensive mediastinal and abdominal metastases have been present for at least the past 27 months. This is the longest reported sur- vival of a patient with this type of neoplasm. Severe preoperative hypertension has been reduced to and maintained at normal blood pressure levels as proven by 5 years observation following successful extirpation of the original growth and the affected kidney. This adds another etiological factor to the causes of hyper- tension in unilateral kidney disease.
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