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Cushing's syndrome with malignant corticotropin-producing tumor
Cushing’s
Syndrome
with Malignant
Corticotropin-Producing Remission and Relapse
FRANK
Tumor
Following Subtotal Adrenalectomy Resection
L. ENGEL,
M.D. and LAWRENCE
Durham,
KAHANA,
*
and Tumor
M.D.~
North Carolina hirsutism, a dorsal hump and a suprasternal mass interpreted as a fat pad. (Fig. 1.) Her blood pressure was 180 to 200!100 to 110 mm. Hg and weight 68 kg. The skin was diffusely pigmented, particularly in exposed areas, in scars on the feet and over the knuckles. The abdomen was distended, but there were no palpable masses and no striae. Laboratory data included a hemoglobin of 12.4 gm. per 100 ml., white blood cell count 20,900 per cu. mm. with 83 per cent polymorphonuclear leukocytes, urine specific gravity 1.009 with a trace of sugar, fasting biood sugar 101 mg. per 100 ml., cholesterol 232 mg. per 100 ml., serum sodium 151.9 mEq. per L., chloride 96.4 mEq. per L., carbon dioxide-combining power 36.6 mEq. per L., and potassium 2.8 mEq. per L. The results of a glucose tolerance test in mg. per 100 ml. were fasting 103, after thirty minutes 183, after one hour 21 I, after two hours 183 and after three hours 128. Urinary excretion of 17-hydroxycorticosteroids and 17-ketosteroids was increased, and there was an exaggerated response to ACTH. (Table I.) Roentgenograms of the chest showed suspicious widening of the superior mediastinum. The spine was osteopocotic. The skull was normal except for some thinning of the posterior clinoids. On March 23, 1955, the entire right and 80 to 90 per cent of the left adrenal gland were removed surgically. On gross examination, both ovaries appeared to be normal. ‘The right adrenal gland weighed 12 gm. and the excised portion of the left gland 9 cm. Sections revealed nodular hyperplasia. In the left adrenal gland there was a microscopic adenoma which had been partially resected. It was poorly encapsulated, and the cells showed a degree of pleomorphism which suggested possible early malignancy.
HE association of Cushing’s syndrome with malignant tumors of the thymus, respiratory tract, pancreas and other tissues has been recognized for a long time. It has attracted special attention recently because of evidence that some of these tumors may be the source of material with adrenocorticotropic activity [I]. Several excellent reviews of previously reported cases have been published recently [Y-5], and hence no effort will be made to summarize them here. The present case is of interest because of several unusual features, most noteworthy of which were the long duration of the illness (seven years), remission after subtotal adrenalectomy followed by relapse, a second remission on removal of a maiignant mediastinal tumor, and final recurrence on regrowth and metastatic spread of the tumor. The tumor was found to contain large amounts of an ACTH-like material [ 71, and activity of the disease was characterized by intense pigmentation of the skin.
T
CASE REPORT A forty-eight year
old woman (C. McC. Duke history No. E06938) was first seen in March 1955. She had a two year history of hypertension, peripheral and facial edema, weakness, aching pain in the extremities and increased appetite, with moderate weight gain. For one year she had had polyuria without polydipsia, metallic taste in the mouth, insomnia, increased hair growth on the face and only two menstrual periods. Physical examination revealed moon-face, facial plethora, central obesity, labial
*From the Department of Medicine and the Division of Endocrinology, Duke University Medical Center, Durham, North Carolina. This study was supported by a Training Grant (2A-5074) from the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, and by a traineeship (L. K.) at Duke University Medical Center by the same Institute (1958-59). Manuscript received April 27, 1962. t Present address: Tampa General Hospital, Tampa, Florida.
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1R
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1c
FIG. 1. A, March 15, 1955, appearance of patient prior to adrenalectomy. I), July 13,1956, appearance at time of recurrence of Cushing’s syndrome with large mediastinal mass. C, September 24, 1957, appearance fourteen months after resection of mediastinal tumor. Note suprasternal mass in 1955 and absence of pigmentation of scar in 1957, at time of remission. Urinary excretion of steroids declined after adrenalectomy. (Table I.) In April 1955 she received radiation therapy directed to the pituitary gland. In May 1955 the blood pressure was 150 to 160/l 00 to 110 mm. Hg, and serum electrolytes and glucose tolerance had become normal. She returned home on a regimen of 12.5 mg. of cortisone acetate every eight hours. By June 1955 a definite decrease in pigmentation was noted, and in October regular menstrual periods were re-established. There was general improvement in her condition. In February 1956 pigmentation began to increase again and soon became intense. About this time she noted the appearance of a goiter, which was firm and tender. During the next few months there was a gradual return of many of her original symptoms but to a lesser degree. Menses remained regular. She found cortisone therapy could be discontinued without adverse symptoms. She was readmitted to the hospital on July 2, 1956, with the additional complaints of dysphagia and hoarseness. Physical examination showed a return of the appearance of Cushing’s syndrome, although it was not as striking as in 1955. (Fig. 1.) Her blood pressure was 180/110 mm. Hg. A very firm, walnut-sized mass was palpated in the isthmus of the thyroid and found to extend beneath the sternum. No enlarged lymph nodes were palpated. There was intense and diffuse skin pigmentation. A roentgenogram of the chest demonstrated a large mass in the anterior mediastinum. The urinary excretion of steroids (Table I) was increased but showed no further rise under ACTH stimulation. The white blood cell count was 13,100 per cu. mm. with 78 per cent polymorphonuclear leukocytes. The fasting blood sugar and serum electrolytes were normal. VOL.
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Radioactive iodine uptake was 15 per cent in twentyfour hours. It was assumed that Cushing’s syndrome had recurred because of either hyperplasia or malignant transformation of the adrenal remnant, and that the mass in the thyroid was probably unrelated. However, because of the unusual firmness of the thyroid, surgical exploration of the neck was decided upon, with the intention of following this up with adrenalectomy. Surgical exploration on July 9, 1956, revealed what was interpreted grossly as a multinodular goiter with substernal extension. The mass was adherent to the trachea but could be freed by blunt dissection and was readily delivered from the anterior mediastinum. On microscopic examination a malignant tumor invading thyroid and lymph nodes was identified. The tumor was not definitely classified, but metastasis from adrenal carcinoma and thymic carcinoma were considered most prominently at this time. (Fig. 2.) Ten days postoperatively the patient experienced a mild but typical Addisonian crisis while undergoing an intravenous ACTH test. Urinary excretion of steroids was found to have fallen sharply since the operation, and there was no response to ACTH. (Table I.) Substitution therapy with cortisone was reinstituted, and the patient returned to her home in Florida. Following removal of the malignant tumor, there was remarkable clearing of the pigmentation and by December 1956 her appearance was normal. Although moderate hypertension persisted, her general condition returned virtually to normal, and she led an active life. She returned for examination in September 1957, at which time she showed no evidences of Cushing’s syndrome. (Fig. 1.) The blood pressure was 140 to
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Malignant
Corticotropin-Producing TABLE URINARY
Tumor-Engel,
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I
EXCRETION
OF STEROIDS
-
I Date
3/12/55 3/13/55 3/14/55 3/23/55 4/3/55 4/4/55 4/5/55 4/6/55 4/7/55 4/a/55 4/9/55 4/10/55 4/11/55 4/12/55 4/25/55 4/26/55 4/2?/55 4/29/55 4/30/55 7/2/56 7/3/56 7/9/56 7/16/56 7/17/56 7/18/56 9/29/56 11/17/56 2/28/57 3/29/57 7/l/57 9/22/57 9/23/57 9/24/57 10/14/58 2/25/59 4/l /59 6/9/59 6/10/59 6/11/59 6/12/59 6/13/59 6/14/59 6/15/59 6/16/59 6/17/59 6/23/59 6/27/59 6/28/59 7/2/59 7/4/59 7/9/59 7/16/59 7/20/59
Treatment
and Comments
None None 25 units ACTH intravenously in 8 hours Subtotal adrenalectomy 37.5 mg. cortisone; 1 mg. Fluro F 37.5 mg. cortisone; 1 mg. Fluoro F 37.5 mg. cortisone; 1 mg. Fluoro F; 40 units ACTH gel 37.5 mg. cortisone; 1 mg. Fluoro F; 40 units ACTH gel 37.5 mg. cortisone; 1 mg. Fluoro F; 40 units ACTH gel 37.5 mg. cortisone; 1 mg. Fluoro F; 40 units ACTH gel 12.5 mg. cortisone; 1 mg. Fluoro F; 40 units ACTH gel No cortisone; 1 mg. Fluoro F; 40 units ACTH gel every No cortisone; 1 mg. Fluoro F; 40 units ACTH gel every No cortisone; 1 mg. Fluoro F; 40 units ACTH gel every No cortisone; 0.5 mg. Fluoro F No cortisone; 0.5 mg. Fluoro F No cortisone; 1 .O mg. Fluoro F Pituitary x-ray therapy started, 37.5 mg. cortisone 37.5 mg. cortisone None 25 units ACTH intravenously in 8 hours Resection of mediastinal tumor None None 25 units ACTH intravenously in 8 hours; crisis 1.0 mg. Fluoro F * 1.O mg. Fluoro F * 1.O mg. Fluoro F * 1.O mg. Fluoro F * 1.0 mg. Fluoro F * 1.0 mg. Fluoro F* 1.0 mg. Fluoro F *., 40 units ACTH gel every 12 hours 1.0 mg. Fluoro F *; 40 units ACTH gel every 12 hours 1.0 mg. Fluoro F* I .O mg. Fiuoro F * 1.0 mg. Fluoro F* Vane Vane 10 units ACTH gel every 12 hours 10 units ACTH gel every 12 hours 10 units ACTH gel every 12 hours None 2 mg. dexamethasone every 8 hours 2 mg. dexamethasone every 8 hours Exploration of mediastinum 1 mg. dexamethasone every 8 hours 1.5 mg. dexamethasonet; 9.6 mg. o,p’ DDDJ 1.5 mg. dexamethasonet; 9.6 mg. o,p’ DDD 1.5 mg. dexamethasonet; 9.6 mg. o,p’ DDD 1.0 mg. dexamethasone; 9.6 mg. o,p’ DDD 1 .O mg. dexamethasone; 9.6 mg. o,p’ DDD 1.0 mg. dexamethasone; 9.6 mg. o,p’ DDD 1.0 mg. dexamethasone; 9.6 mg. o,p’ DDD
mg. per 24 hours
17-Hydroxycorticosteroids
17-Ketosteroids
42.0 35.0 60.0
26 .b 42.0
. every 12 every 12 every 12 every 12 every 12 12 hours 12 hours 12 hours
15.4 16.0 10.5 8.9 12.3 20.2 20.2 15.7 5.9 7.8 2.2 1.2 1.4 8.7 9.9 13.0 14.3
hours hours hours hours hours
‘8’.; 10.7
3.g 3.9 7.4 9.3 12.2 7.2 8.6 7.2 9.9 13.7 10.2 10.8 14.9
3.3 2.5 3.7 1.9 4.6 3.9 3.6 5.1 4.9 6.0 6.3 8.1 8.3 11.9 12.6 13.7 14.1 14.1 16.7 16.3 10.4 13.2
14.1 10.0 12.0 11 .o 12.4 13.2 8.0 8.8
15.7 18.4 15.1 9.5 3.4 5.6 5.5 6.6
2.9 0.8 4.2 2.0 1.8 3.1 1.1 3.4
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(Continued)
EXCRETION
OF STEROIDS mg. per 24 hours
Date
Treatment
and Comments 17-Ketosteroids
17-Hydroxycorticosteroids
a/10/59 g/30/59 9/15/59 9/21/59 10/5/59 11/12/59 3/17/60 5/8/60 6/25/60
1.0 1.0 1.0 1.0 1.0 8.0 1.0 1.0 0.5
mg. mg. mg. mg. mg. mg. mg. mg. mg.
dexamethasone; dexamethasone; dexamethasone; dexamethasone; dexamethasone; dexamethasone dexamethasone dexamethasone; dexamethasone;
9.6 mg. o,p’ DDD 6.0 mg. o,p’ DDD No DDD for 2 weeks No DDD for 3 weeks No DDD for 3 weeks daily for 3 days no DDD no DDD
10.5 8.4 7.7 6.6 8.1 5.6 7.1 9.2 5.1
6.0 5.3 4.8 4.6 6.3 6.3 8.0 5.6 3.2 L
* Fluorohydrocortisone was administered only during the twenty-four-hour period preceding and during the day of urine collection. Otherwise the patient was receiving 12.5 mg. of cortisone acetate every twelve hours. t Dexamethasone was administered in place of cortisone just prior to and during the day of urine collection. $ 2, 2-his (2-chlorophenyl-4-chlorophenyl) 1-l dichloroethane. 160/90 to 100 mm. Hg. There was normal pigmentation of exposed areas consistent with exposure to Florida sun. No pigmentation had developed in the scar on the neck. No evidence of recurrence of the tumor was found on physical examination or roentgenogram. However, the urinary excretion of steroids was within a normal range while the patient was receiving no cortisone and did not increase in response to ACTH stimulation. The patient found she could go as long as seven days without cortisone but was advised against doing so. In April 1958 a gradual, progressive increase in pigmentation began, and there was some increase in weight. Over the course of the next year, however, the only complaint was increasing pigmentation. A gradual rise in the urinary excretion of steroids was
FIG. 2. Photomicrograph of section of mecliastinal Original magnification X 657. VOL.
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tumor.
noted. Chest roentgenograms obtained in June and October 1958 were interpreted as being within normal limits by her local physician. In June 1959, three years after removal of the mediastinal tumor, she returned to Duke Hospital for re-evaluation, and on roentgenographic examination was found to have a recurrence of the mediastinal tumor as well as two discrete densities in the peripheral lung fields. Review of the roentgenograms made in 1958 showed that these abnormalities were already apparent and had been overlooked. A roentgenogram of the skull showed a normal sella turcica. Her blood pressure was 160/90 mm. Hg. Her general appearance did not suggest Cushing’s syndrome, but there was intense pigmentation of the skin, buccal mucous membranes (Fig. 3) and the dorsum of the tongue. The white blood cell count was 9,400 per cu. mm. with 69 per cent polymorphonuclear leukocytes.
FIG. 3. Buccal pigmentation,
1959.
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Blood glucose and electrolyte levels were normal, but results of the glucose tolerance test (in mg. per 100 ml.) showed mild impairment: fasting 93, after thirty minutes 158, after one hour 163, after two hours 140 and after three hours 108. Urinary steroid levels (Table I) were elevated, considering that subtotal adrenalectomy had been performed. There was no response to either ACTH or dexamethasone. In view of the previous prolonged remission following surgical removal of tumor in the neck and mediastinum in 1956, an attempt was made on June 17, 1959, to remove the recurrent mediastinal and pulmonary tumors, but this did not prove feasible. The tumor was adherent to neighboring structures, and multiple pulmonary metastases were palpated. Histologically the tumor was identical with that removed in 1956. On the assumption that the tumor might be metastatic from an adrenal carcinoma, therapy with daily doses of 6 to 10 gm. of o,p’ DDD (2,2-bis(2chlorophenyl-4-chlorophenyl)l-1 dichloroethane) was begun on June 27, 1959, and continued for two months. The patient tolerated this medication poorly because of anorexia and nausea. There was a modest drop in the urinary excretion of steroids which, however, persisted even after o,p’ DDD therapy had been discontinued for three weeks. Between December 1959 and June 1960 she received 2 to 6 gm. of DDD daily, with occasional interruptions because of nausea. There was little change in the tumor in the lungs until May 1960 when several new, small densities appeared and, in addition, skin nodules were noted. Thereafter, there was slow, progressive deterioration in the patient’s condition, with weight loss, increasing pigmentation and weakness. The patient died in January 1961. Postmortem examination at the Tampa General Hospital showed extensive tumor involvement of both ovaries, myocardium, lungs, liver, breast, lymph nodes, skin and thyroid. No thymus gland tissue was found, and the hilar lymph nodes were not enlarged. On the left side 4 gm. of adrenal tissue was found; none was found on the right side. The pituitary gland was not examined. Histologically, sections of the tumor tissue from various sites showed a pattern which was identidal with that of the tissue removed from the mediastinum and neck in 1956 and in 1959. Its appearance coincided with that of the tumors variously diagnosed as bronchial adenoma, thymoma and oat cell tumor [S] in a group of patients with Cushing’s syndrome. The adrenal remnant showed hyperplasia, with some areas of cellular pleomorphism comparable to those noted in 1955, but no evidence of primary or metastatic carcinoma. COMMENTS
The diagnosis of Cushing’s syndrome was obvious in 1955, and treatment by subtotal adrenalectomy and pituitary gland radiation
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seemed the most practical approach. The possibility of a thymic tumor was considered seriously, but its relevance to the case was not appreciated at this time. Retrospectively, it is clear that the tumor which was removed subsequently in 1956 was actually present in 1955. Moreover, the suprasternal mass, clearly visible in Figure 1, really was an extension of the tumor rather than a fat pad. Thus there was a reasonably close temporal association between the tumor and the development of Cushing’s syndrome. Judging from the urinary steroid levels while the patient was receiving ACTH gel after subtotal adrenalectomy, the adrenal remnant was responsive. Urinary excretion of 17-hydroxycorticosteroids ranged between 1.2 and 2.3 mg. per twenty-four hours when the patient did not receive cortisone or ACTH, and between 5.9 and 15.7 mg. per twenty-four hours when she received 40 units of ACTH gel twice a day. The decrease in pigmentation which lasted for several months after adrenalectomy is remarkable and unexplained. The recurrence of Cushing’s syndrome in 1956 was characterized by progressive pigmentation and by rising levels of steroid excretion; there was no response to the administration of ACTH presumably because the adrenal remnant was responding maximally. The development of adrenal crisis and the fall in the urinary steroids f o 11owing removal of the mediastinal tumor were unexpected and were the first indication that the tumor bore a causal relationship to Cushing’s syndrome. The negligible response of urinary excretion of steroids to an eight-hour infusion of ACTH postoperatively, coupled with the pathologist’s interpretation of the mediastinal tumor as a metastasis from an adrenal cortical carcinoma, led us to believe that the tumor was the chief source of the steroids and that, in all likelihood, there was little active adrenal tissue remaining on the left side. If one assumes that the preoperative steroid values were accounted for solely by stimulation from tumor “ACTH,” even with the later knowledge that the mediastinal tumor was the source of some adrenal-stimulating material, why the adrenal remnant did not respond more vigorously to ACTH therapy is puzzling. The explanation that the ACTH infusion subjected the gland to stimulation for only eight hours, whereas the tumor stimulated it for twenty-four hours, is not acceptable. The adrenal glands were responsive to an eight-hour infusion of ACTH preoperaAMERICAN
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tively in 1955. A later study (September 1957), in which 40 units of ACTH gel were administered every twelve hours for two days, likewise failed to show an increase in steroid excretion. The adrenal remnant responded to ACTH gel therapy in 1955. The possibility that the tumor was the source of “ACTH,” however, was not suggested until later in 1956, when the pigmentation dramatically disappeared after removal of the mediastinal tumor. It was reinforced when the pigmentation reappeared pari passu with slowly rising steroid levels in 1958 and 1959 and with recurrence of the tumor with pulmonary metastases. Studies in June 1959 again did not show a response to 80 units of ACTH gel administered for three days or to suppressive doses of dexamethasone. This was interpreted to mean either that the tumor was autonomous and the sole source of both the steroids and ACTH (or melanophore stimulating hormone (MSH)), or that the tumor secreted ACTH and the adrenal remnant was responding maximally. Several attempts to obtain plasma ACTH assays in 1959 were unsuccessful, but tumor and plasma stored frozen since 1959 were assayed by Dr. Grant Liddle of Vanderbilt University in 1961 and found to have increased amounts of adrenal-stimulating activity. The tumor assayed 125 milliunits per gm. and the plasma 0.7 milliunits per 100 ml. (normal < 0.5 milliunits per 100 ml.) [I]. Treatment with o,p’ lIDI> during 1959 and 1961) was based on the view that the origin of the mediastinal tumor might be the adrenal cortex. Although steroid values were reduced somewhat by this treatment, there was never any definite evidence of the agent having any effect on the tumor, which slowly progressed, its rate of growth certainly being more rapid than in the period of 1956 to 1959. With the passage of time the interpretation that the tumor was producing steroids as well as ACTH became less tenable and was not supported by the autopsy findings. The adrenal remnant was hyperplastic and did not show any evidence of carcinoma, whereas the malignant tumor was widespread. Unfortunately, no tissue was saved for analysis of hormone content. Our final interpretation is that Cushing’s syndrome was due to a mediastinal tumor of uncertain origin which produced an ACTH-like substance. The present case differs from the majority of the reported cases of Cushing’s syndrome assoVOL.
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ciated with malignant tumors in its prolonged course and relatively low order of malignancy. Most authors have emphasized the fulminating course of both the Cushing’s syndrome and the tumor when the two have occurred together. One such patient with an oat cell carcinoma and elevated plasma ACTH titer has recently been seen at this hospital and is included in the series published by Meador et al. [I]. Among the seventy-two reported cases of Cushing’s syndrome with malignant and benign non-endocrine tumors we have found ten cases in which the relatively prolonged course and other features were similar to those in our case [3,5-121. Norris (71 reported the autopsy findings in a patient previously diagnosed as having Cushing’s syndrome due to adrenal hyperplasia by Walters, Wilder and Kepler [13]. The patient, a thirty-one year old woman, had the signs and symptoms of Cushing’s syndrome in 1933. When examined at the Mayo Clinic in 1934 pigmentation and hypokalemic alkalosis were noted. A partial, bilateral resection of hyperplastic adrenal tissue was carried out. For several months following the operation there was some improvement, and then Cushing’s syndrome recurred. Her course over four years was one of repeated one of the latter relapses and remissions, occurring following x-ray therapy over the thymic region, even though no tumor had been observed. Remissions were associated with lightening of the skin and relapses with intensification of pigmentation. Autopsy revealed a tumor involving the mediastinum, lungs, liver, adrenals and right ovary. The adrenals were hyperplastic. Norris considered the ovarian tumor as primary and classified it as an arrhenoblastoma, largely because of the endocrinopathy. The diagnosis of arrhenoblastoma does not seem justified from the photomicrographs published; rather, this would appear to be another example of an epithelial tumor of undetermined origin. Another particularly relevant case is that of Edmunds et al., first published in 1958 as an example of Cushing’s syndrome with pigmentation and hypokalemic alkalosis and again in 1961 as a case of breast carcinoma following adrenalectomy for Cushing’s syndrome [S,14]. The patient was a forty-two year old woman in whom Cushing’s syndrome developed in 1956. Progressive pigmentation was a prominent symptom, and the plasma ACTH level was elevated. The left adrenal gland and 90 per cent
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of the right adrenal gland were removed; this was followed by a dramatic improvement, including virtually complete loss of pigmentation. However, two years later intense pigmentation recurred, and again plasma ACTH levels were elevated. However, in contrast to our patient, there was no evidence of adrenal activation. Thirty-three months after adrenalectomy, bilateral ovarian tumors were found on laparotomy, and a large mediastinal mass was recognized. Shortly thereafter a tumor of the breast was removed and interpreted as the primary carcinoma. Unfortunately, no autopsy was performed. However, the tumor distribution in this patient was similar to that in our patient. The authors permitted us to review the microscopic sections of this tumor. We found them to be virtually indistinguishable from those in the present case. As previously noted, the tumor was found in the breast of our patient at autopsy. Taken by itself, this could have been interpreted as a primary lobular carcinoma of the breast. However, the historic data in our case belie this interpretation, and we are more inclined to interpret the breast lesion as a late metastasis. In our case, the primary lesion in the mediastinum could easily have been overlooked for several years had it not presented itself externally in the neck. We wonder whether this may not also hold true in Edmunds’ case. Scholz and Bahn’s patient [ 771 had symptoms of Cushing’s syndrome beginning in 1952, subtotal adrenalectomy in July 1954, first evidence of a mediastinal tumor in March 1955 and died one year later. Her skin was deeply pigmented and, at autopsy, she had hyperplasia of the adrenal remnant. MacPhee’s patient [70] had symptoms for two years before subtotal adrenalectomy was performed. Widening of the mediastinum was noted at the time of surgery. As in our case, there was a good response to adrenalectomy, but ten months later the signs of Cushing’s syndrome recurred. A large mediastinal mass and occluding carcinoma of the bronchus of the upper lobe of the right lung were found. The patient died thirteen months later. The author did not mention pigmentation. Bagshawe [3] described a patient who had a transient period of pigmentation following which Gushing’s syndrome developed with hypokalemic alkalosis. Total adrenalectomy was performed twenty-one months after onset. Six months later, cervical lymphadenopathy was noted and proved to be carcinoma, either
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bronchogenic or thymogenic. Subsequently the patient had persistent diarrhea and hepatic enlargement and exhibited an increased urinary excretion of 5-hydroxyindoleacetic acid. He died two and a half years after adrenalectomy; permission for postmortem examination was not obtained (personal communication). The association of Gushing’s syndrome with the carcinoid syndrome has been noted previously [7,75-771. Cohen et al. [S] described two patients from whom bronchial adenomas were removed two and four years, respectively, after subtotal adrenalectomy for Cushing’s syndrome. The first patient had no evidences of Cushing’s syndrome at the time the bronchial adenoma was removed, whereas the second had a relapse three years after subtotal adrenalectomy. An adrenal adenoma was found then and removed, but Cushing’s syndrome did not abate completely until after the bronchial adenoma was resected. The patients described by Frank [8] and by Kracht and Hantschmann [5] are of particular interest, since in both the tumor was diagnosed by a biopsy of the lymph node three years before the onset of Cushing’s syndrome; they died one year later. Pigmentation was present in both patients. Recently Albright [72] reported a case of malignant melanoma which developed after bilateral adrenalectomy for Cushing’s syndrome; this also may belong in this group. The patient was a thirty-one year old man whose illness extended over a three year period. Pigmentation, diabetes mellitus and psychosis were the presenting manifestations, and there was marked hypokalemic alkalosis. Following bilateral removal of hyperplastic adrenal glands the features of Cushing’s syndrome subsided, and pigmentation decreased markedly. Thirteen months after adrenalectomy he was found to have a mass in the anterior mediastinum, an enlarged supraclavicular lymph node and recurrence of pigmentation. Biopsy of the lymph node yielded tissue interpreted as metastatic amelanotic melanoblastoma. No primary lesion was demonstrated among a number of darkly pigmented nevi of the skin which were biopsied. The patient died one year later, having had progressively intense pigmentation, steady enlargement of the mediastinal tumor and widespread pulmonary and bone metastases. Permission for postmortem examination was not obtained. Dr. Albright permitted us to review the section of the biopsy AMERICAN
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Malignant Corticotropin-Producing specimen of the lymph node. While the appearance of the tissue may be considered compatible with the diagnosis of melanoma, the similarity with the tissue in our case, in that of Edmunds et al. [74], and in those reported by Cohen et al. [6] is striking. The tumors in all these cases were variously labeled as thymic carcinoma, bronchogenic carcinoma, oat cell carcinoma, bronchial adenoma, arrhenoblastoma and adenocarcinoma of the breast, but when photomicrographs were available it was apparent that the tumors were probably all the same. Cohen et al. [6], in comparing the appearance of the sections from their patients with bronchial adenoma, thymomas and oat cell tumors with Cushing’s syndrome, have emphasized their basic similarity, if not identity, and suggest that they all arise from a common cell type. An unusual feature in our patient, as well as in several others, was the temporary loss of pigmentation following subtotal adrenalectomy and coincident with clinical remission. This was true in the patients of Norris [7] and Edmunds et al. [9], in the latter it was sufficiently striking to prompt Px-unty to comment, “The features of this case appear to contradict all the ‘laws’ of endocrinology” [78]. In Norris’ patient the impression is that pigmentation waxed and waned with what appeared to be spontaneous relapses and remissions. In Bagshawe’s patient was [31,on the other hand, pigmentation transient prior to the development of Cushing’s syndrome. The demonstration of ACTH-like material in the tumor and plasma of several patients with tumors [1,3,9,79] clearly implicates this substance as being responsible for both the adrenal hyperactivity and the pigmentation. In these particular patients, at least, the long-standing question concerning the primacy of the tumor in the etiology of Cushing’s syndrome has seemingly been answered. It should not, however, be assumed that this mechanism is operative in all cases or that the material in the tumor is chemically identical with adenohypophyseal ACTH. The elucidation of the structures of ACTH and MSH has given an explanation for the ability of both peptides to cause pigmentation. Recent studies indicate that alterations in the structure of ACTH may differentially influence its adrenal-stimulating and MSH-like activities [ZO]. It is conceivable that these tumors synthesize and release a variety of peptides VOL. 34,
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which share certain structural features with ACTH and MSH but do not possess these biological activities in the same degree and proportions as the natural hormones. The relatively prolonged course in our patient and in several of the others suggests that some of these cases may fall in a different category from the majority in which progression of the tumor and/or Cushing’s syndrome has generally been precipitous. Our patient survived seven years, three years after metastases were detected. Since manifestations of Gushing’s syndrome in these patients often preceded, by months or years, discovery of the tumor, which even when present grew with extraordinary slowness, it is probable that these tumors begin while they are still small. to secrete “ACTH” Judging from Norris’ case [7], one also wonders whether spontaneous fluctuations in hormone secretion may not occur, which would account for remissions in Cushing’s syndrome. In the diagnosis of this type of Cushing’s syndrome, use is made of the fact that the urinary excretion of steroids is not suppressed by large doses of dexamethasone but may still respond to ACTH stimulation. This contrasts with the situation in patients with adrenal tumors who generally are unresponsive to both dexamethasone and ACTH [7]. In evaluating patients with Cushing’s syndrome the existence of a tumor of the type described herein must be considered along with the more conventional causes of the disorder. The presence of pigmentation and of hypokalemic alkalosis may be important clues. The inability to suppress steroid excretion with large doses of dexamethasone, hyperresponsivity to ACTH and elevated plasma ACTH values should be of diagnostic value. Demonstration and removal of the tumor rather than adrenalectomy should be the treatment of choice. SUMMARY
A case of Cushing’s syndrome due to a malignant ACTH-secreting mediastinal tumor and adrenal hyperplasia with long survival is reported. The case was characterized by intense pigmentation and hypokalemic alkalosis. Remission of Cushing’s syndrome and pigmentation followed subtotal adrenalectomy, with recurrence a year later as the mediastinal tumor grew and extended. A second remission followed resection of the mediastinal tumor and lasted almost two years. The patient died three years after the appearance of the first metastases.
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Intense pigmentation characterized the period of active tumor growth. Large amounts of ACTH-active material were extracted from the mediastinal tumor. Serial studies of steroid excretion and of responses to ACTH and dexamethasone therapy over a five-year period are recorded. Acknowledgment: We are indebted to Dr. Grant Liddle, Vanderbilt University School of Medicine, for performing the ACTH assays on the patient’s plasma and tumor, and to Dr. Bernard Fetter, Duke University, for helpful discussions of the pathologic material. REFERENCES 1. MEADOR, C. K., LIDDLE, G. W., ISLAND, D. P., NICHOLSON,W. E., LUCAS, C. P., NUCKTON,J. and LUETSCHER,J. A. On the cause of Cushing’s syndrome in patients with tumors arising from nonendocrine tissue. J Clin. Endocrinol. 22: 693, 1962. 2. ALLOTT, E. N. and SKELTON, M. 0. Increased adrenocortical activity associated with malignant disease. Loncet, 2: 278, 1960. 3. BAGSHAWE, K. D. Hypokalaemia, carcinoma and Gushing’s syndrome. Lancet, 2: 284, 1960. 4, BORNSTEIN,P., NOLAN, J. P. and BERNANKE,D. Adrenocortical hyperfunction in association with anaplastic carcinoma of the respiratory tract. New England J. Med., 264: 363, 1961. 5. KRACHT, J. and HANTSCHMANN,N. Tumorsyntropien des Cushing-Syndroms. Acta endocrinol., 38: 490, 1961. 6. COHEN, R. B., TOLL, G. D. and CASTLEMAN,B. Bronchial adenomas in Gushing’s syndrome: their relation to thymomas and oat cell carcinomas associated with hyperadrenocorticism. Cancer, 13: 812, 1960. 7. NORRIS, E. H. Arrhenoblastoma: a malignant ovarian tumor associated with endocrinological effects. Am. J. Cancer, 32: 1, 1938.
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8. FRANK, El. Thymuskarzinom mit Cushingschem Syndrom. (Der Thymogene Morbus Gushing). Schweiz. med. Wchnschr., 75: 152, 1945. 9. EDMUNDS,A. W. B., MCKEOWN, K. C. and COLEMAN, P. N. A case of Cushing’s syndrome with pigmentation and severe hypokalaemic alkalosis. J. Clin. Path., 11: 237, 1958. 10. MACPHEE, I. W. Cushing’s syndrome associated with carcinoma of the bronchus. Brit. J. Surg., 46: 456, 1959. 11. SCHOLZ, D. A. and BAHN, R. C. Thymic tumors associated with Cushing’s syndrome: review of three cases. Pm. Staj Meet. Mayo Clin., 34: 433, 1959. 12. ALBRIGHT, E. C. Malignant melanoma following bilateral adrenalectomy for Cushing’s syndrome. J. Clin. End&ml., 22: 93, 1962. 13. WALTERS, W., WILDER, R. M. and KEPLER, E. J. The suprarenal cortical syndrome: report of two cases, with successful surgical treatment. Pm. Staff Meet. Mayo Clin., 9: 400, 1934. 14. EDMUNDS;A. W. B., MCKEOWN, K. C. and COLEMAN, P. N. Carcinoma of breast after adrenalectomy for Cushing’s syndrome. Brit. M. J., 2: 807, 1961. 15. HARRISON, M. T., MONTGOMERY,D. A., RAMSEY, A. S., ROBERTSON,J. H. and WELBOURN, R. B. Cushing’s syndrome with carcinoma of bronchus and with features suggesting carcinoid tumor. Loncet, 1: 23, 1957. 16. ESCOVITZ,W. E. and REINGOLD,I. M. Functioning malignant bronchial carcinoid with Cushing’s syndrome and recurrent sinus arrest. Ann. Znt. Med., 54: 1248, 1961. 17. DAVIS, R. B. and KENNEDY, B. J. Carcinoid syndrome associated with adrenal hyperplasia. Arch. Znt. Med., 109: 192, 1962. 18. PRUNTY, F. T. G. The interpretation of hormonal abnormalities. Proc. Z?oy. Sot. Med., 51: 1073, 1958. 19. CHRISTY, N. P. Adrenocorticotrophic activity in the plasma of patients with Cushing’s syndrome associated with pulmonary neoplasms. Lancet, 1: 85, 1961. 20. ENGEL, F. L. Extra-adrenal actions of adrenocorticotropin. Vitamins 63 Hormones, 19: 189, 1961
AMERICAN
JOURNAL
OF MEDICINE
Syndrome
with Malignant
Corticotropin-Producing Remission and Relapse
FRANK
Tumor
Following Subtotal Adrenalectomy Resection
L. ENGEL,
M.D. and LAWRENCE
Durham,
KAHANA,
*
and Tumor
M.D.~
North Carolina hirsutism, a dorsal hump and a suprasternal mass interpreted as a fat pad. (Fig. 1.) Her blood pressure was 180 to 200!100 to 110 mm. Hg and weight 68 kg. The skin was diffusely pigmented, particularly in exposed areas, in scars on the feet and over the knuckles. The abdomen was distended, but there were no palpable masses and no striae. Laboratory data included a hemoglobin of 12.4 gm. per 100 ml., white blood cell count 20,900 per cu. mm. with 83 per cent polymorphonuclear leukocytes, urine specific gravity 1.009 with a trace of sugar, fasting biood sugar 101 mg. per 100 ml., cholesterol 232 mg. per 100 ml., serum sodium 151.9 mEq. per L., chloride 96.4 mEq. per L., carbon dioxide-combining power 36.6 mEq. per L., and potassium 2.8 mEq. per L. The results of a glucose tolerance test in mg. per 100 ml. were fasting 103, after thirty minutes 183, after one hour 21 I, after two hours 183 and after three hours 128. Urinary excretion of 17-hydroxycorticosteroids and 17-ketosteroids was increased, and there was an exaggerated response to ACTH. (Table I.) Roentgenograms of the chest showed suspicious widening of the superior mediastinum. The spine was osteopocotic. The skull was normal except for some thinning of the posterior clinoids. On March 23, 1955, the entire right and 80 to 90 per cent of the left adrenal gland were removed surgically. On gross examination, both ovaries appeared to be normal. ‘The right adrenal gland weighed 12 gm. and the excised portion of the left gland 9 cm. Sections revealed nodular hyperplasia. In the left adrenal gland there was a microscopic adenoma which had been partially resected. It was poorly encapsulated, and the cells showed a degree of pleomorphism which suggested possible early malignancy.
HE association of Cushing’s syndrome with malignant tumors of the thymus, respiratory tract, pancreas and other tissues has been recognized for a long time. It has attracted special attention recently because of evidence that some of these tumors may be the source of material with adrenocorticotropic activity [I]. Several excellent reviews of previously reported cases have been published recently [Y-5], and hence no effort will be made to summarize them here. The present case is of interest because of several unusual features, most noteworthy of which were the long duration of the illness (seven years), remission after subtotal adrenalectomy followed by relapse, a second remission on removal of a maiignant mediastinal tumor, and final recurrence on regrowth and metastatic spread of the tumor. The tumor was found to contain large amounts of an ACTH-like material [ 71, and activity of the disease was characterized by intense pigmentation of the skin.
T
CASE REPORT A forty-eight year
old woman (C. McC. Duke history No. E06938) was first seen in March 1955. She had a two year history of hypertension, peripheral and facial edema, weakness, aching pain in the extremities and increased appetite, with moderate weight gain. For one year she had had polyuria without polydipsia, metallic taste in the mouth, insomnia, increased hair growth on the face and only two menstrual periods. Physical examination revealed moon-face, facial plethora, central obesity, labial
*From the Department of Medicine and the Division of Endocrinology, Duke University Medical Center, Durham, North Carolina. This study was supported by a Training Grant (2A-5074) from the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, and by a traineeship (L. K.) at Duke University Medical Center by the same Institute (1958-59). Manuscript received April 27, 1962. t Present address: Tampa General Hospital, Tampa, Florida.
726
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1A
1R
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1c
FIG. 1. A, March 15, 1955, appearance of patient prior to adrenalectomy. I), July 13,1956, appearance at time of recurrence of Cushing’s syndrome with large mediastinal mass. C, September 24, 1957, appearance fourteen months after resection of mediastinal tumor. Note suprasternal mass in 1955 and absence of pigmentation of scar in 1957, at time of remission. Urinary excretion of steroids declined after adrenalectomy. (Table I.) In April 1955 she received radiation therapy directed to the pituitary gland. In May 1955 the blood pressure was 150 to 160/l 00 to 110 mm. Hg, and serum electrolytes and glucose tolerance had become normal. She returned home on a regimen of 12.5 mg. of cortisone acetate every eight hours. By June 1955 a definite decrease in pigmentation was noted, and in October regular menstrual periods were re-established. There was general improvement in her condition. In February 1956 pigmentation began to increase again and soon became intense. About this time she noted the appearance of a goiter, which was firm and tender. During the next few months there was a gradual return of many of her original symptoms but to a lesser degree. Menses remained regular. She found cortisone therapy could be discontinued without adverse symptoms. She was readmitted to the hospital on July 2, 1956, with the additional complaints of dysphagia and hoarseness. Physical examination showed a return of the appearance of Cushing’s syndrome, although it was not as striking as in 1955. (Fig. 1.) Her blood pressure was 180/110 mm. Hg. A very firm, walnut-sized mass was palpated in the isthmus of the thyroid and found to extend beneath the sternum. No enlarged lymph nodes were palpated. There was intense and diffuse skin pigmentation. A roentgenogram of the chest demonstrated a large mass in the anterior mediastinum. The urinary excretion of steroids (Table I) was increased but showed no further rise under ACTH stimulation. The white blood cell count was 13,100 per cu. mm. with 78 per cent polymorphonuclear leukocytes. The fasting blood sugar and serum electrolytes were normal. VOL.
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Radioactive iodine uptake was 15 per cent in twentyfour hours. It was assumed that Cushing’s syndrome had recurred because of either hyperplasia or malignant transformation of the adrenal remnant, and that the mass in the thyroid was probably unrelated. However, because of the unusual firmness of the thyroid, surgical exploration of the neck was decided upon, with the intention of following this up with adrenalectomy. Surgical exploration on July 9, 1956, revealed what was interpreted grossly as a multinodular goiter with substernal extension. The mass was adherent to the trachea but could be freed by blunt dissection and was readily delivered from the anterior mediastinum. On microscopic examination a malignant tumor invading thyroid and lymph nodes was identified. The tumor was not definitely classified, but metastasis from adrenal carcinoma and thymic carcinoma were considered most prominently at this time. (Fig. 2.) Ten days postoperatively the patient experienced a mild but typical Addisonian crisis while undergoing an intravenous ACTH test. Urinary excretion of steroids was found to have fallen sharply since the operation, and there was no response to ACTH. (Table I.) Substitution therapy with cortisone was reinstituted, and the patient returned to her home in Florida. Following removal of the malignant tumor, there was remarkable clearing of the pigmentation and by December 1956 her appearance was normal. Although moderate hypertension persisted, her general condition returned virtually to normal, and she led an active life. She returned for examination in September 1957, at which time she showed no evidences of Cushing’s syndrome. (Fig. 1.) The blood pressure was 140 to
728
Malignant
Corticotropin-Producing TABLE URINARY
Tumor-Engel,
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I
EXCRETION
OF STEROIDS
-
I Date
3/12/55 3/13/55 3/14/55 3/23/55 4/3/55 4/4/55 4/5/55 4/6/55 4/7/55 4/a/55 4/9/55 4/10/55 4/11/55 4/12/55 4/25/55 4/26/55 4/2?/55 4/29/55 4/30/55 7/2/56 7/3/56 7/9/56 7/16/56 7/17/56 7/18/56 9/29/56 11/17/56 2/28/57 3/29/57 7/l/57 9/22/57 9/23/57 9/24/57 10/14/58 2/25/59 4/l /59 6/9/59 6/10/59 6/11/59 6/12/59 6/13/59 6/14/59 6/15/59 6/16/59 6/17/59 6/23/59 6/27/59 6/28/59 7/2/59 7/4/59 7/9/59 7/16/59 7/20/59
Treatment
and Comments
None None 25 units ACTH intravenously in 8 hours Subtotal adrenalectomy 37.5 mg. cortisone; 1 mg. Fluro F 37.5 mg. cortisone; 1 mg. Fluoro F 37.5 mg. cortisone; 1 mg. Fluoro F; 40 units ACTH gel 37.5 mg. cortisone; 1 mg. Fluoro F; 40 units ACTH gel 37.5 mg. cortisone; 1 mg. Fluoro F; 40 units ACTH gel 37.5 mg. cortisone; 1 mg. Fluoro F; 40 units ACTH gel 12.5 mg. cortisone; 1 mg. Fluoro F; 40 units ACTH gel No cortisone; 1 mg. Fluoro F; 40 units ACTH gel every No cortisone; 1 mg. Fluoro F; 40 units ACTH gel every No cortisone; 1 mg. Fluoro F; 40 units ACTH gel every No cortisone; 0.5 mg. Fluoro F No cortisone; 0.5 mg. Fluoro F No cortisone; 1 .O mg. Fluoro F Pituitary x-ray therapy started, 37.5 mg. cortisone 37.5 mg. cortisone None 25 units ACTH intravenously in 8 hours Resection of mediastinal tumor None None 25 units ACTH intravenously in 8 hours; crisis 1.0 mg. Fluoro F * 1.O mg. Fluoro F * 1.O mg. Fluoro F * 1.O mg. Fluoro F * 1.0 mg. Fluoro F * 1.0 mg. Fluoro F* 1.0 mg. Fluoro F *., 40 units ACTH gel every 12 hours 1.0 mg. Fluoro F *; 40 units ACTH gel every 12 hours 1.0 mg. Fluoro F* I .O mg. Fiuoro F * 1.0 mg. Fluoro F* Vane Vane 10 units ACTH gel every 12 hours 10 units ACTH gel every 12 hours 10 units ACTH gel every 12 hours None 2 mg. dexamethasone every 8 hours 2 mg. dexamethasone every 8 hours Exploration of mediastinum 1 mg. dexamethasone every 8 hours 1.5 mg. dexamethasonet; 9.6 mg. o,p’ DDDJ 1.5 mg. dexamethasonet; 9.6 mg. o,p’ DDD 1.5 mg. dexamethasonet; 9.6 mg. o,p’ DDD 1.0 mg. dexamethasone; 9.6 mg. o,p’ DDD 1 .O mg. dexamethasone; 9.6 mg. o,p’ DDD 1.0 mg. dexamethasone; 9.6 mg. o,p’ DDD 1.0 mg. dexamethasone; 9.6 mg. o,p’ DDD
mg. per 24 hours
17-Hydroxycorticosteroids
17-Ketosteroids
42.0 35.0 60.0
26 .b 42.0
. every 12 every 12 every 12 every 12 every 12 12 hours 12 hours 12 hours
15.4 16.0 10.5 8.9 12.3 20.2 20.2 15.7 5.9 7.8 2.2 1.2 1.4 8.7 9.9 13.0 14.3
hours hours hours hours hours
‘8’.; 10.7
3.g 3.9 7.4 9.3 12.2 7.2 8.6 7.2 9.9 13.7 10.2 10.8 14.9
3.3 2.5 3.7 1.9 4.6 3.9 3.6 5.1 4.9 6.0 6.3 8.1 8.3 11.9 12.6 13.7 14.1 14.1 16.7 16.3 10.4 13.2
14.1 10.0 12.0 11 .o 12.4 13.2 8.0 8.8
15.7 18.4 15.1 9.5 3.4 5.6 5.5 6.6
2.9 0.8 4.2 2.0 1.8 3.1 1.1 3.4
AMERICAN
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Corticotropin-Producing TABLE URINARY
I
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729
(Continued)
EXCRETION
OF STEROIDS mg. per 24 hours
Date
Treatment
and Comments 17-Ketosteroids
17-Hydroxycorticosteroids
a/10/59 g/30/59 9/15/59 9/21/59 10/5/59 11/12/59 3/17/60 5/8/60 6/25/60
1.0 1.0 1.0 1.0 1.0 8.0 1.0 1.0 0.5
mg. mg. mg. mg. mg. mg. mg. mg. mg.
dexamethasone; dexamethasone; dexamethasone; dexamethasone; dexamethasone; dexamethasone dexamethasone dexamethasone; dexamethasone;
9.6 mg. o,p’ DDD 6.0 mg. o,p’ DDD No DDD for 2 weeks No DDD for 3 weeks No DDD for 3 weeks daily for 3 days no DDD no DDD
10.5 8.4 7.7 6.6 8.1 5.6 7.1 9.2 5.1
6.0 5.3 4.8 4.6 6.3 6.3 8.0 5.6 3.2 L
* Fluorohydrocortisone was administered only during the twenty-four-hour period preceding and during the day of urine collection. Otherwise the patient was receiving 12.5 mg. of cortisone acetate every twelve hours. t Dexamethasone was administered in place of cortisone just prior to and during the day of urine collection. $ 2, 2-his (2-chlorophenyl-4-chlorophenyl) 1-l dichloroethane. 160/90 to 100 mm. Hg. There was normal pigmentation of exposed areas consistent with exposure to Florida sun. No pigmentation had developed in the scar on the neck. No evidence of recurrence of the tumor was found on physical examination or roentgenogram. However, the urinary excretion of steroids was within a normal range while the patient was receiving no cortisone and did not increase in response to ACTH stimulation. The patient found she could go as long as seven days without cortisone but was advised against doing so. In April 1958 a gradual, progressive increase in pigmentation began, and there was some increase in weight. Over the course of the next year, however, the only complaint was increasing pigmentation. A gradual rise in the urinary excretion of steroids was
FIG. 2. Photomicrograph of section of mecliastinal Original magnification X 657. VOL.
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tumor.
noted. Chest roentgenograms obtained in June and October 1958 were interpreted as being within normal limits by her local physician. In June 1959, three years after removal of the mediastinal tumor, she returned to Duke Hospital for re-evaluation, and on roentgenographic examination was found to have a recurrence of the mediastinal tumor as well as two discrete densities in the peripheral lung fields. Review of the roentgenograms made in 1958 showed that these abnormalities were already apparent and had been overlooked. A roentgenogram of the skull showed a normal sella turcica. Her blood pressure was 160/90 mm. Hg. Her general appearance did not suggest Cushing’s syndrome, but there was intense pigmentation of the skin, buccal mucous membranes (Fig. 3) and the dorsum of the tongue. The white blood cell count was 9,400 per cu. mm. with 69 per cent polymorphonuclear leukocytes.
FIG. 3. Buccal pigmentation,
1959.
730
Malignant
Corticotropin-Producing
Blood glucose and electrolyte levels were normal, but results of the glucose tolerance test (in mg. per 100 ml.) showed mild impairment: fasting 93, after thirty minutes 158, after one hour 163, after two hours 140 and after three hours 108. Urinary steroid levels (Table I) were elevated, considering that subtotal adrenalectomy had been performed. There was no response to either ACTH or dexamethasone. In view of the previous prolonged remission following surgical removal of tumor in the neck and mediastinum in 1956, an attempt was made on June 17, 1959, to remove the recurrent mediastinal and pulmonary tumors, but this did not prove feasible. The tumor was adherent to neighboring structures, and multiple pulmonary metastases were palpated. Histologically the tumor was identical with that removed in 1956. On the assumption that the tumor might be metastatic from an adrenal carcinoma, therapy with daily doses of 6 to 10 gm. of o,p’ DDD (2,2-bis(2chlorophenyl-4-chlorophenyl)l-1 dichloroethane) was begun on June 27, 1959, and continued for two months. The patient tolerated this medication poorly because of anorexia and nausea. There was a modest drop in the urinary excretion of steroids which, however, persisted even after o,p’ DDD therapy had been discontinued for three weeks. Between December 1959 and June 1960 she received 2 to 6 gm. of DDD daily, with occasional interruptions because of nausea. There was little change in the tumor in the lungs until May 1960 when several new, small densities appeared and, in addition, skin nodules were noted. Thereafter, there was slow, progressive deterioration in the patient’s condition, with weight loss, increasing pigmentation and weakness. The patient died in January 1961. Postmortem examination at the Tampa General Hospital showed extensive tumor involvement of both ovaries, myocardium, lungs, liver, breast, lymph nodes, skin and thyroid. No thymus gland tissue was found, and the hilar lymph nodes were not enlarged. On the left side 4 gm. of adrenal tissue was found; none was found on the right side. The pituitary gland was not examined. Histologically, sections of the tumor tissue from various sites showed a pattern which was identidal with that of the tissue removed from the mediastinum and neck in 1956 and in 1959. Its appearance coincided with that of the tumors variously diagnosed as bronchial adenoma, thymoma and oat cell tumor [S] in a group of patients with Cushing’s syndrome. The adrenal remnant showed hyperplasia, with some areas of cellular pleomorphism comparable to those noted in 1955, but no evidence of primary or metastatic carcinoma. COMMENTS
The diagnosis of Cushing’s syndrome was obvious in 1955, and treatment by subtotal adrenalectomy and pituitary gland radiation
Tumor-&gel,
Kuhana
seemed the most practical approach. The possibility of a thymic tumor was considered seriously, but its relevance to the case was not appreciated at this time. Retrospectively, it is clear that the tumor which was removed subsequently in 1956 was actually present in 1955. Moreover, the suprasternal mass, clearly visible in Figure 1, really was an extension of the tumor rather than a fat pad. Thus there was a reasonably close temporal association between the tumor and the development of Cushing’s syndrome. Judging from the urinary steroid levels while the patient was receiving ACTH gel after subtotal adrenalectomy, the adrenal remnant was responsive. Urinary excretion of 17-hydroxycorticosteroids ranged between 1.2 and 2.3 mg. per twenty-four hours when the patient did not receive cortisone or ACTH, and between 5.9 and 15.7 mg. per twenty-four hours when she received 40 units of ACTH gel twice a day. The decrease in pigmentation which lasted for several months after adrenalectomy is remarkable and unexplained. The recurrence of Cushing’s syndrome in 1956 was characterized by progressive pigmentation and by rising levels of steroid excretion; there was no response to the administration of ACTH presumably because the adrenal remnant was responding maximally. The development of adrenal crisis and the fall in the urinary steroids f o 11owing removal of the mediastinal tumor were unexpected and were the first indication that the tumor bore a causal relationship to Cushing’s syndrome. The negligible response of urinary excretion of steroids to an eight-hour infusion of ACTH postoperatively, coupled with the pathologist’s interpretation of the mediastinal tumor as a metastasis from an adrenal cortical carcinoma, led us to believe that the tumor was the chief source of the steroids and that, in all likelihood, there was little active adrenal tissue remaining on the left side. If one assumes that the preoperative steroid values were accounted for solely by stimulation from tumor “ACTH,” even with the later knowledge that the mediastinal tumor was the source of some adrenal-stimulating material, why the adrenal remnant did not respond more vigorously to ACTH therapy is puzzling. The explanation that the ACTH infusion subjected the gland to stimulation for only eight hours, whereas the tumor stimulated it for twenty-four hours, is not acceptable. The adrenal glands were responsive to an eight-hour infusion of ACTH preoperaAMERICAN
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tively in 1955. A later study (September 1957), in which 40 units of ACTH gel were administered every twelve hours for two days, likewise failed to show an increase in steroid excretion. The adrenal remnant responded to ACTH gel therapy in 1955. The possibility that the tumor was the source of “ACTH,” however, was not suggested until later in 1956, when the pigmentation dramatically disappeared after removal of the mediastinal tumor. It was reinforced when the pigmentation reappeared pari passu with slowly rising steroid levels in 1958 and 1959 and with recurrence of the tumor with pulmonary metastases. Studies in June 1959 again did not show a response to 80 units of ACTH gel administered for three days or to suppressive doses of dexamethasone. This was interpreted to mean either that the tumor was autonomous and the sole source of both the steroids and ACTH (or melanophore stimulating hormone (MSH)), or that the tumor secreted ACTH and the adrenal remnant was responding maximally. Several attempts to obtain plasma ACTH assays in 1959 were unsuccessful, but tumor and plasma stored frozen since 1959 were assayed by Dr. Grant Liddle of Vanderbilt University in 1961 and found to have increased amounts of adrenal-stimulating activity. The tumor assayed 125 milliunits per gm. and the plasma 0.7 milliunits per 100 ml. (normal < 0.5 milliunits per 100 ml.) [I]. Treatment with o,p’ lIDI> during 1959 and 1961) was based on the view that the origin of the mediastinal tumor might be the adrenal cortex. Although steroid values were reduced somewhat by this treatment, there was never any definite evidence of the agent having any effect on the tumor, which slowly progressed, its rate of growth certainly being more rapid than in the period of 1956 to 1959. With the passage of time the interpretation that the tumor was producing steroids as well as ACTH became less tenable and was not supported by the autopsy findings. The adrenal remnant was hyperplastic and did not show any evidence of carcinoma, whereas the malignant tumor was widespread. Unfortunately, no tissue was saved for analysis of hormone content. Our final interpretation is that Cushing’s syndrome was due to a mediastinal tumor of uncertain origin which produced an ACTH-like substance. The present case differs from the majority of the reported cases of Cushing’s syndrome assoVOL.
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ciated with malignant tumors in its prolonged course and relatively low order of malignancy. Most authors have emphasized the fulminating course of both the Cushing’s syndrome and the tumor when the two have occurred together. One such patient with an oat cell carcinoma and elevated plasma ACTH titer has recently been seen at this hospital and is included in the series published by Meador et al. [I]. Among the seventy-two reported cases of Cushing’s syndrome with malignant and benign non-endocrine tumors we have found ten cases in which the relatively prolonged course and other features were similar to those in our case [3,5-121. Norris (71 reported the autopsy findings in a patient previously diagnosed as having Cushing’s syndrome due to adrenal hyperplasia by Walters, Wilder and Kepler [13]. The patient, a thirty-one year old woman, had the signs and symptoms of Cushing’s syndrome in 1933. When examined at the Mayo Clinic in 1934 pigmentation and hypokalemic alkalosis were noted. A partial, bilateral resection of hyperplastic adrenal tissue was carried out. For several months following the operation there was some improvement, and then Cushing’s syndrome recurred. Her course over four years was one of repeated one of the latter relapses and remissions, occurring following x-ray therapy over the thymic region, even though no tumor had been observed. Remissions were associated with lightening of the skin and relapses with intensification of pigmentation. Autopsy revealed a tumor involving the mediastinum, lungs, liver, adrenals and right ovary. The adrenals were hyperplastic. Norris considered the ovarian tumor as primary and classified it as an arrhenoblastoma, largely because of the endocrinopathy. The diagnosis of arrhenoblastoma does not seem justified from the photomicrographs published; rather, this would appear to be another example of an epithelial tumor of undetermined origin. Another particularly relevant case is that of Edmunds et al., first published in 1958 as an example of Cushing’s syndrome with pigmentation and hypokalemic alkalosis and again in 1961 as a case of breast carcinoma following adrenalectomy for Cushing’s syndrome [S,14]. The patient was a forty-two year old woman in whom Cushing’s syndrome developed in 1956. Progressive pigmentation was a prominent symptom, and the plasma ACTH level was elevated. The left adrenal gland and 90 per cent
732
Malignant
Corticotropin-Producing
of the right adrenal gland were removed; this was followed by a dramatic improvement, including virtually complete loss of pigmentation. However, two years later intense pigmentation recurred, and again plasma ACTH levels were elevated. However, in contrast to our patient, there was no evidence of adrenal activation. Thirty-three months after adrenalectomy, bilateral ovarian tumors were found on laparotomy, and a large mediastinal mass was recognized. Shortly thereafter a tumor of the breast was removed and interpreted as the primary carcinoma. Unfortunately, no autopsy was performed. However, the tumor distribution in this patient was similar to that in our patient. The authors permitted us to review the microscopic sections of this tumor. We found them to be virtually indistinguishable from those in the present case. As previously noted, the tumor was found in the breast of our patient at autopsy. Taken by itself, this could have been interpreted as a primary lobular carcinoma of the breast. However, the historic data in our case belie this interpretation, and we are more inclined to interpret the breast lesion as a late metastasis. In our case, the primary lesion in the mediastinum could easily have been overlooked for several years had it not presented itself externally in the neck. We wonder whether this may not also hold true in Edmunds’ case. Scholz and Bahn’s patient [ 771 had symptoms of Cushing’s syndrome beginning in 1952, subtotal adrenalectomy in July 1954, first evidence of a mediastinal tumor in March 1955 and died one year later. Her skin was deeply pigmented and, at autopsy, she had hyperplasia of the adrenal remnant. MacPhee’s patient [70] had symptoms for two years before subtotal adrenalectomy was performed. Widening of the mediastinum was noted at the time of surgery. As in our case, there was a good response to adrenalectomy, but ten months later the signs of Cushing’s syndrome recurred. A large mediastinal mass and occluding carcinoma of the bronchus of the upper lobe of the right lung were found. The patient died thirteen months later. The author did not mention pigmentation. Bagshawe [3] described a patient who had a transient period of pigmentation following which Gushing’s syndrome developed with hypokalemic alkalosis. Total adrenalectomy was performed twenty-one months after onset. Six months later, cervical lymphadenopathy was noted and proved to be carcinoma, either
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bronchogenic or thymogenic. Subsequently the patient had persistent diarrhea and hepatic enlargement and exhibited an increased urinary excretion of 5-hydroxyindoleacetic acid. He died two and a half years after adrenalectomy; permission for postmortem examination was not obtained (personal communication). The association of Gushing’s syndrome with the carcinoid syndrome has been noted previously [7,75-771. Cohen et al. [S] described two patients from whom bronchial adenomas were removed two and four years, respectively, after subtotal adrenalectomy for Cushing’s syndrome. The first patient had no evidences of Cushing’s syndrome at the time the bronchial adenoma was removed, whereas the second had a relapse three years after subtotal adrenalectomy. An adrenal adenoma was found then and removed, but Cushing’s syndrome did not abate completely until after the bronchial adenoma was resected. The patients described by Frank [8] and by Kracht and Hantschmann [5] are of particular interest, since in both the tumor was diagnosed by a biopsy of the lymph node three years before the onset of Cushing’s syndrome; they died one year later. Pigmentation was present in both patients. Recently Albright [72] reported a case of malignant melanoma which developed after bilateral adrenalectomy for Cushing’s syndrome; this also may belong in this group. The patient was a thirty-one year old man whose illness extended over a three year period. Pigmentation, diabetes mellitus and psychosis were the presenting manifestations, and there was marked hypokalemic alkalosis. Following bilateral removal of hyperplastic adrenal glands the features of Cushing’s syndrome subsided, and pigmentation decreased markedly. Thirteen months after adrenalectomy he was found to have a mass in the anterior mediastinum, an enlarged supraclavicular lymph node and recurrence of pigmentation. Biopsy of the lymph node yielded tissue interpreted as metastatic amelanotic melanoblastoma. No primary lesion was demonstrated among a number of darkly pigmented nevi of the skin which were biopsied. The patient died one year later, having had progressively intense pigmentation, steady enlargement of the mediastinal tumor and widespread pulmonary and bone metastases. Permission for postmortem examination was not obtained. Dr. Albright permitted us to review the section of the biopsy AMERICAN
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Malignant Corticotropin-Producing specimen of the lymph node. While the appearance of the tissue may be considered compatible with the diagnosis of melanoma, the similarity with the tissue in our case, in that of Edmunds et al. [74], and in those reported by Cohen et al. [6] is striking. The tumors in all these cases were variously labeled as thymic carcinoma, bronchogenic carcinoma, oat cell carcinoma, bronchial adenoma, arrhenoblastoma and adenocarcinoma of the breast, but when photomicrographs were available it was apparent that the tumors were probably all the same. Cohen et al. [6], in comparing the appearance of the sections from their patients with bronchial adenoma, thymomas and oat cell tumors with Cushing’s syndrome, have emphasized their basic similarity, if not identity, and suggest that they all arise from a common cell type. An unusual feature in our patient, as well as in several others, was the temporary loss of pigmentation following subtotal adrenalectomy and coincident with clinical remission. This was true in the patients of Norris [7] and Edmunds et al. [9], in the latter it was sufficiently striking to prompt Px-unty to comment, “The features of this case appear to contradict all the ‘laws’ of endocrinology” [78]. In Norris’ patient the impression is that pigmentation waxed and waned with what appeared to be spontaneous relapses and remissions. In Bagshawe’s patient was [31,on the other hand, pigmentation transient prior to the development of Cushing’s syndrome. The demonstration of ACTH-like material in the tumor and plasma of several patients with tumors [1,3,9,79] clearly implicates this substance as being responsible for both the adrenal hyperactivity and the pigmentation. In these particular patients, at least, the long-standing question concerning the primacy of the tumor in the etiology of Cushing’s syndrome has seemingly been answered. It should not, however, be assumed that this mechanism is operative in all cases or that the material in the tumor is chemically identical with adenohypophyseal ACTH. The elucidation of the structures of ACTH and MSH has given an explanation for the ability of both peptides to cause pigmentation. Recent studies indicate that alterations in the structure of ACTH may differentially influence its adrenal-stimulating and MSH-like activities [ZO]. It is conceivable that these tumors synthesize and release a variety of peptides VOL. 34,
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which share certain structural features with ACTH and MSH but do not possess these biological activities in the same degree and proportions as the natural hormones. The relatively prolonged course in our patient and in several of the others suggests that some of these cases may fall in a different category from the majority in which progression of the tumor and/or Cushing’s syndrome has generally been precipitous. Our patient survived seven years, three years after metastases were detected. Since manifestations of Gushing’s syndrome in these patients often preceded, by months or years, discovery of the tumor, which even when present grew with extraordinary slowness, it is probable that these tumors begin while they are still small. to secrete “ACTH” Judging from Norris’ case [7], one also wonders whether spontaneous fluctuations in hormone secretion may not occur, which would account for remissions in Cushing’s syndrome. In the diagnosis of this type of Cushing’s syndrome, use is made of the fact that the urinary excretion of steroids is not suppressed by large doses of dexamethasone but may still respond to ACTH stimulation. This contrasts with the situation in patients with adrenal tumors who generally are unresponsive to both dexamethasone and ACTH [7]. In evaluating patients with Cushing’s syndrome the existence of a tumor of the type described herein must be considered along with the more conventional causes of the disorder. The presence of pigmentation and of hypokalemic alkalosis may be important clues. The inability to suppress steroid excretion with large doses of dexamethasone, hyperresponsivity to ACTH and elevated plasma ACTH values should be of diagnostic value. Demonstration and removal of the tumor rather than adrenalectomy should be the treatment of choice. SUMMARY
A case of Cushing’s syndrome due to a malignant ACTH-secreting mediastinal tumor and adrenal hyperplasia with long survival is reported. The case was characterized by intense pigmentation and hypokalemic alkalosis. Remission of Cushing’s syndrome and pigmentation followed subtotal adrenalectomy, with recurrence a year later as the mediastinal tumor grew and extended. A second remission followed resection of the mediastinal tumor and lasted almost two years. The patient died three years after the appearance of the first metastases.
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Intense pigmentation characterized the period of active tumor growth. Large amounts of ACTH-active material were extracted from the mediastinal tumor. Serial studies of steroid excretion and of responses to ACTH and dexamethasone therapy over a five-year period are recorded. Acknowledgment: We are indebted to Dr. Grant Liddle, Vanderbilt University School of Medicine, for performing the ACTH assays on the patient’s plasma and tumor, and to Dr. Bernard Fetter, Duke University, for helpful discussions of the pathologic material. REFERENCES 1. MEADOR, C. K., LIDDLE, G. W., ISLAND, D. P., NICHOLSON,W. E., LUCAS, C. P., NUCKTON,J. and LUETSCHER,J. A. On the cause of Cushing’s syndrome in patients with tumors arising from nonendocrine tissue. J Clin. Endocrinol. 22: 693, 1962. 2. ALLOTT, E. N. and SKELTON, M. 0. Increased adrenocortical activity associated with malignant disease. Loncet, 2: 278, 1960. 3. BAGSHAWE, K. D. Hypokalaemia, carcinoma and Gushing’s syndrome. Lancet, 2: 284, 1960. 4, BORNSTEIN,P., NOLAN, J. P. and BERNANKE,D. Adrenocortical hyperfunction in association with anaplastic carcinoma of the respiratory tract. New England J. Med., 264: 363, 1961. 5. KRACHT, J. and HANTSCHMANN,N. Tumorsyntropien des Cushing-Syndroms. Acta endocrinol., 38: 490, 1961. 6. COHEN, R. B., TOLL, G. D. and CASTLEMAN,B. Bronchial adenomas in Gushing’s syndrome: their relation to thymomas and oat cell carcinomas associated with hyperadrenocorticism. Cancer, 13: 812, 1960. 7. NORRIS, E. H. Arrhenoblastoma: a malignant ovarian tumor associated with endocrinological effects. Am. J. Cancer, 32: 1, 1938.
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8. FRANK, El. Thymuskarzinom mit Cushingschem Syndrom. (Der Thymogene Morbus Gushing). Schweiz. med. Wchnschr., 75: 152, 1945. 9. EDMUNDS,A. W. B., MCKEOWN, K. C. and COLEMAN, P. N. A case of Cushing’s syndrome with pigmentation and severe hypokalaemic alkalosis. J. Clin. Path., 11: 237, 1958. 10. MACPHEE, I. W. Cushing’s syndrome associated with carcinoma of the bronchus. Brit. J. Surg., 46: 456, 1959. 11. SCHOLZ, D. A. and BAHN, R. C. Thymic tumors associated with Cushing’s syndrome: review of three cases. Pm. Staj Meet. Mayo Clin., 34: 433, 1959. 12. ALBRIGHT, E. C. Malignant melanoma following bilateral adrenalectomy for Cushing’s syndrome. J. Clin. End&ml., 22: 93, 1962. 13. WALTERS, W., WILDER, R. M. and KEPLER, E. J. The suprarenal cortical syndrome: report of two cases, with successful surgical treatment. Pm. Staff Meet. Mayo Clin., 9: 400, 1934. 14. EDMUNDS;A. W. B., MCKEOWN, K. C. and COLEMAN, P. N. Carcinoma of breast after adrenalectomy for Cushing’s syndrome. Brit. M. J., 2: 807, 1961. 15. HARRISON, M. T., MONTGOMERY,D. A., RAMSEY, A. S., ROBERTSON,J. H. and WELBOURN, R. B. Cushing’s syndrome with carcinoma of bronchus and with features suggesting carcinoid tumor. Loncet, 1: 23, 1957. 16. ESCOVITZ,W. E. and REINGOLD,I. M. Functioning malignant bronchial carcinoid with Cushing’s syndrome and recurrent sinus arrest. Ann. Znt. Med., 54: 1248, 1961. 17. DAVIS, R. B. and KENNEDY, B. J. Carcinoid syndrome associated with adrenal hyperplasia. Arch. Znt. Med., 109: 192, 1962. 18. PRUNTY, F. T. G. The interpretation of hormonal abnormalities. Proc. Z?oy. Sot. Med., 51: 1073, 1958. 19. CHRISTY, N. P. Adrenocorticotrophic activity in the plasma of patients with Cushing’s syndrome associated with pulmonary neoplasms. Lancet, 1: 85, 1961. 20. ENGEL, F. L. Extra-adrenal actions of adrenocorticotropin. Vitamins 63 Hormones, 19: 189, 1961
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