Clinical and Pathophysiologic Aspects of Adrenocortical Carcinoma
MORTIMER B. LIPSETT, M.D., ROY HERTZ, M.D., PH.D. and GRIFF T. Ross, M.D., PH.D. Bethesda, Maryland
C ARCINOMA of the adrenal cortex is one of the rarer cancers in man, accounting for less than 0.2 per cent of the deaths from cancer in one large series [1]. Because of this low incidence, it has been difficult for any single group to obtain extensive experience with this disease. The many scattered case reports of adrenal tumors, including those recorded between 1930 and 1949, were collected and ably reviewed by Rapaport et al. [2]. In the next five years, Heinbecker et al. [3] found eighty-three more cases recorded in the literature and added ten of their own. In the largest and most carefully studied series of patients with adrenal cortical carcinoma, MacFarlane [4] analyzed the data on the charts of fifty-five patients who had been treated in four London teaching hospitals. We have had the opportunity to study and treat thirty-eight patients with adrenal carcinoma and will discuss some of the features of diagnosis, pathophysiology, prognosis and treatment. Since most of the patients referred to us had metastatic disease, there is a distinct factor of case selection in this report. However, a comparison of features of this series with those of MacFarlane’s reveals a marked similarity between the two groups of patients.
METHODS
In each case the diagnosis of adrenal cortical carcinoma was confirmed by us by histologic examina- tion of sections from either the primary tumor or metastatic deposits. The following methods were used for routine steroid determinations: urinary 17-ketosteroids (17-KS) [5]; urinary 17-hydroxy- corticoids (17-OHCS) [6]; plasma corticoids [7]. Several additional urinary steroids of particular
interest have been measured and the methods reported elsewhere [8,9].
In the past, adrenal cortical cancer has been classified as functional or nonfunctional, depending on the presence or absence of recognizable clinical syndromes due to excessive secretion of steroids. It is now apparent that the patient with adrenal cancer may excrete large amounts of 17-KS and 17-OHCS in the urine without necessarily having evidence of androgen or corticoid excess. Therefore, in this discus- sion we shall consider a cancer functional if steroid production by the tumor can be demonstrated by chemical means. Functional cancers may be divided further according to the clinical syndromes produced.
We have recorded virilization when one or more of the following sequelae of androgen excess were present: temporal hair recession, male pattern bald- ness, increased facial hair not of the lanugo type, deepening of the voice, loss of female fat distribution and concomitant muscular changes, and clitoral hypertrophy. The adult male, of course, rarely presents clinical manifestations of excessive androgen secretion. The clinical criteria that lead to a diagnosis of Cushing’s syndrome are now too generally known to require enumeration herc.
RESULTS AND COMMENTS
Clinical Features. Age and sex: The age at the time of diagnosis varied throughout the life span (Fig. 1), the youngest patient being twelve months old, the oldest sixty-two years old. Twenty-three of the thirty-eight patients were females. The increased susceptibility to adrenal cancer in females is similar to that noted in Cushing’s syndrome due to either adrenal hyper- plasia or adenoma [10]. This similarity is even more striking when the sex incidence of adrenal cancers that produce Cushing’s syndrome in adults is analyzed. The data in Table I, derived
* From the Endocrinology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Manuscript received October 29, 1962.
| Reference | Cushing's Syndrome | No Endocrine Syndrome | ||
|---|---|---|---|---|
| Male | Female | Male | Female | |
| Wood et al. [17] | 7 | 1 | ||
| Heinbecker et al. [3]. | 2 | 2 | 1 | |
| Knight et al. [12] | 3 | 4 | ||
| Birke et al. [13] | 1 | 2 | 0 | 3 |
| Rapaport et al. [2] | ||||
| Collected series | 5 | 52 | 16 | 12 |
| Uncollected series | 2 | 2 | 3 | 2 |
| MacFarlane [4] | 4 | 18 | 13 | 5 |
| This series | 3 | 12 | 8 | 1 |
| Totals | 15 | 88 | 52 | 29 |
from several series, reveal a great predominance of women in this group (eighty-eight women to fifteen men), which may in part be due to the ease with which the diagnosis of Cushing’s syndrome is made in women.
In the group of patients without clinical manifestations of excess hormonc secretion, the incidence in males was higher (Table 1). Of eighty-one cases of adrenal carcinoma, collected from nine series, fifty-two occurred in males.
It is noteworthy that in our series the cancers originated on the left side in twenty-four instances. The more frequent origin of adrenal carcinoma from the left adrenal gland was also noted by Rapaport et al. [2] and MacFarlane [4].
Presenting complaints: The presenting com- plaints were those associated with the syndromes of virilization, Cushing’s syndrome or precocious puberty. In women, the initial complaints were most often due to hirsutism, acne, plethora and centripetal obesity. Weight gain and menstrual disturbances were frequently noted. The hyper- tension associated with Cushing’s syndrome occasionally initiated investigation. Insulin re- sistance led to the diagnosis in one instance. One man was treated for polycythemia for two years before the appearance of an abdominal mass led to biopsy and the diagnosis of adrenal cancer. Since the polycythemia in this patient was not accompanied by leukocytosis, thrombo- cytosis or splenomegaly, it is presumed that this man exhibited only one effect of excessive androgen secretion, erythremia. The develop- ment of acne in a twenty-seven year old man
6
₡ Z NUMBER OF PATIENTS
Female
5
Male
4
3
2
1
0
0-10
11-20
21-30
31-40
41-50
51-60
61-70
AGE
likewise may have been caused by excessive androgen secretion.
In patients without endocrine syndromes, abdominal discomfort, pain, distention and the presence of an abdominal mass led to the diagnosis.
Endocrine syndromes: Adrenal carcinoma can produce in the appropriate subject the following syndromcs: feminization, virilization, Cushing’s syndrome, precocious puberty or combinations of these, and, rarely, hypoglycemia. We have not encountered any patients with feminizing adrenal carcinoma. The relatively few case reports on this syndrome have been reviewed by Wallach et al. [14]. Hypoglycemia has not been associated with adrenal carcinoma in our patients. When this does occur, it most probably is not a result of the secretion of a particular steroid by the tumor, but has same genesis as the hypoglycemia accompanying large retroperi- toneal tumors. Three patients with this syn- drome have been described recently by Williams et al. [15].
The distribution of endocrine syndromes is charted in Figure 2. The combination of Cush- ing’s syndrome and virilization was most com- mon, only one woman having Cushing’s syn- drome alone. Virilization without signs of Cushing’s syndrome occurred in three women and three children. In these three children the initial diagnosis was precocious puberty, the cause of which became apparent after further study.
Urinary steroid excretion: When neoplastic transformation takes place in the adrenal cortex, many of the enzyme systems concerned with
CUSHING’S SYNDROME
0
CUSHING’S SYNDROME + VIRILIZATION
0
Women
VIRILIZATION
0
Men
Children
NO
ENDOCRINE SYNDROME
1
3
5
7
9
11
13
15
17
NUMBER OF PATIENTS
steroid biosynthesis are retained by the tumor. It is important to re-emphasize that the adrenal cancer does not cause the development of new enzyme systems capable of synthesizing steroids not produced by the normal adrenal gland. Rather, the presence of large amounts of un- usual steroids in the urine reflects inefficient use of the normal steroid precursors by the neo- plasm, and increased excretion of the metabolites normally present in only trace amounts.
When an adrenal cancer produces steroids, the patient almost invariably excretes large amounts of 17-KS. This is true whether the tumor causes Cushing’s syndrome, virilization or feminization, or is unaccompanied by signifi- cant clinical features of endocrinopathy. The urinary excretion of 17-KS occasionally exceeds 1.0 gm. per twenty-four hours, but daily twenty- four hour levels in the range of 50 to 200 mg. are more frequent. In general, 17-OHCS excretion also is increased in this disease, although urinary levels may be normal when 17-KS excretion is high. (Fig. 3.) 17-OHCS excretion, as measured by the Porter-Silber method, is seldom as high as 17-KS excretion. The presence of normal levels
| Subjects | Elevated 17-KS | Viriliza- tion | Elevated 17-OHCS | Cushing's Syndrome |
|---|---|---|---|---|
| Men | 7 | 0 | 6 | 3 |
| Women | 19 | 18 | 18 | 15 |
| Children | 7 | 6 | 3 | 3 |
* Figures represent number of patients.
500
AVERAGE URINARY 17-KS MG. / 24 HOURS
Normal 17 - OHCS
200
100
70
50
40
30
20
10
7
5
Normal 17 - KS
4
3
2
.
1
2
3
4
5
7
10
20
30
40 50
70
100
200 300
AVERAGE URINARY 17-OHCS MG. /24 HOURS
of 17-OHCS in the urine does not necessarily imply that the unaffected adrenal gland is the source, since we have shown [16] that adrenal cancer may produce 17-OHCS in amounts that yield normal urinary levels.
Table II correlates steroid excretion and the clinical state. Since the adult male cannot be virilized further, there is no clinical correlate of excessive androgen excretion in this group, with the possible exception of the patient with poly- cythemia already mentioned. Thus if only precursors of 17-KS are produced by the tumor, it will usually appear to be nonfunctioning in the adult male.
There was no clinical evidence of excessive steroid secretion in ten patients, eight of whom were men. Four of these eight men had high urinary levels of 17-KS and three of the four also excreted large amounts of 17-OHCS.
Not even in women or children is the degree of virilization well correlated with 17-KS excre- tion. It should be recalled that virilization is caused by the secretion of an androgen, and that the urinary 17-KS are derived from both andro- genic and nonandrogenic precursors. Thus, unless either the cancer secretes enough andro- gen or there is sufficient peripheral transforma- tion of a nonandrogenic steroid such as dehydro- epiandrosterone (DHEA) to an androgen, virilization will not occur. Since the secretion rate of testosterone in the normal male is 4 to 10 mg. per twenty-four hours, production of a
| Etiology | Age of Onset | Sex | Virilization | Mass in Upper Quadrant | Suprarenal Mass | Size of Mass | |
|---|---|---|---|---|---|---|---|
| Female | Male | ||||||
| Carcinoma | Any | 5 | 1 | Usual; severe | Present in 44% of our patients | Usual* | Large |
| Adenoma | Adult | 2 | 1 | Rare: mild | None | Occasional | Small |
| Hyperplasia | Adult | 4 | 1 | Rare; mild | None | None | |
* By intravenous pyelography, found in thirty-nine of thirty-nine cases.
| Etiology | 17-KS (mg./24 hr.) | 17-OHCS (mg./24 hr.) | Response of 17-OHCS to ACTH | Suppression by Steroids | Increased DHEA * Excretion | Increased Tetrahydro S Excretion |
|---|---|---|---|---|---|---|
| Carcinoma | 25-800 | 15-200 | Occasional | No | 17/17f | 13/13 |
| Adenoma | 3-15 | 15-45 | Occasional | No | Rare | No |
| Hyperplasia | 10-40 | 13-25 | Hyperresponsive | Usual | Rare | Small |
* Dehydroepiandrosterone.
f Reported by others in 80 to 90 per cent of cases.
few milligrams of testosterone would suffice to virilize a woman, but the 17-KS derived from this would be a negligible fraction of the total 17-KS excreted in the urine of patients with adrenal cancer.
Similarly, Cushing’s syndrome is not the invariable accompaniment of increased excre- tion of 17-OHCS. Compounds that are not derived from cortisol are included in the urinary 17-OHCS whether the method em- ployed to measure 17-OHCS is that of Porter- Silber or one of the many modifications of the Norymberski technic [17]. Thus the secretion of cortisol may be normal when 17-OHCS excretion is high. Such a case was reported recently [16].
Diagnosis. In Tables III and Iv we have sum- marized certain important diagnostic features of the adrenal carcinoma that produces the clinical picture of Cushing’s syndrome. When Cushing’s syndrome occurs in a child, adrenal carcinoma is the most frequent cause: whereas in the adult, adrenal hyperplasia is the most frequent cause. Virilization is usually mild and occurs infrequently in patients with adenoma or hyperplasia, but in patients with adrenal cancer it is a usual occurrence and may be severe. The
presence of a large suprarenal mass in a patient with Cushing’s syndrome is almost pathog- nomonic of adrenal cancer. In twenty patients, the actual or estimated weight of the tumor was over 500 gm. The large size of these tumors is emphasized by the finding of a palpable mass in the upper quadrant in 44 per cent of our patients. In each of our patients a suprarenal mass was demonstrated by routine intravenous pyelography. This is in sharp contrast to the difficulty in demonstrating the adenoma causing Cushing’s syndrome. It has been reported that some adenomas, weighing 100 to 200 gm., have caused virilization as well as Cushing’s syn- drome. Whether these are adrenal cancers of low malignancy is still a vexing point for pathologists, but biochemically their behavior differs from the usual small adenoma that causes Cushing’s syndrome.
There are several differences in steroid excretion among the entities causing Cushing’s syndrome. 17-KS excretion is usually highest in patients with adrenal carcinoma, although a few patients with Cushing’s syndrome asso- ciated with other neoplasms have had high urinary levels of 17-KS. Only when 17-OHCS excretion is very high is adrenal carcinoma
20
Adenoma
MG. PER 24 HOURS
Normal + ACTH
Carcinoma
Hyperplasia
15
17-OHCS
Tetrahydro S
10
Normal
5
0
(5)
(2)
(3)
(5)
[13)
suggested. There is usually a considerable over- lap in the amount of 17-OHCS excreted in the urine among the three groups.
The response to ACTH is of limited use in distinguishing adenoma from carcinoma, since occasional responses have been noted in both. Six of our patients with adrenal cancer have responded to an eight hour infusion of 25 units of ACTH by doubling the plasma corticoids and substantially increasing the urinary corticoids.
Inability to depress steroid excretion by the daily administration of 8 mg. of dexamethasone, or its equivalent, strongly supports the possi- bility of neoplasia but does not distinguish between adenoma and carcinoma. Although we have not seen clear-cut suppression in twenty- four patients with adrenal carcinoma who were tested, it has been described in one patient by Gallagher et al. [18]. The considerable daily fluctuation in steroid output of patients with adrenal cancer requires that either marked or substantial suppression be obtained before con- cluding that the result of the suppression test is positive.
Division of the ketosteroids into an a and B fraction by digitonin precipitation has been recognized as a valuable test for determining the presence of adrenal carcinoma, and a review of 17-KS excretion in disease [19] reenforced this observation. Since the ß-ketosteroids are com- posed in large part of DHEA, determination of this 17-KS has the same significance. We have found DHEA excretion to be increased in each of sixteen patients tested. This is not invariably true, however, and others [4,18,20,21] have found DHEA excretion to be normal in occa- sional patients with adrenal carcinoma and increased 17-KS excretion.
The excretion of large amounts of tetrahydro substance S (THS) in the urine of two patients with adrenal cancer was first demonstrated by Rosselot et al. [22], and subsequently confirmed in other patients with adrenal carcinoma [8,23]. We have shown that it may be the major 17-OHCS in the urine in this disease, and have reported that every one of thirteen patients with increased levels of 17-OHCS in the urine had increased levels of THS [16]. Since this does not occur except to a minor extent in Cushing’s syndrome due to adrenal hyperplasia or adrenal adenoma, or after ACTH stimulation of the normal gland, the determination of THS excretion may be an important differential diagnostic feature. In Figure 4 the relative amounts of THS in the urine with respect to the total 17-OHCS excreted in the urine have been summarized.
We have discussed the significance of THS excretion elsewhere [16]. Briefly, the enzyme systems involved in steroid biosynthesis in adrenal cancer are less efficient than those in the normal gland, so that the normal precursors which do not ordinarily reach the peripheral circulation are released from the tumor in large amounts. The metabolites of these substances partially account for the abnormal pattern of steroid excretion in adrenal cancer. In Figure 5, the last step in the synthesis of cortisol is shown. If substance S cannot be converted efficiently to cortisol, THS is excreted in the urine. This block in 118-hydroxylation may be partial or com- plete; such a complete block was demonstrated in one patient with adrenal carcinoma [16].
SUBSTANCE S
CORTISOL
CH20H
CH2OH
C-0
OH
C - 0
OH
--- OH
ADRENAL
0
0-
CH2OH
CH2OH
C - 0
OH
C - 0
0
---- DH
URINE
OH
OH
TETRAHYDRO SUBSTANCE 5
TETRAHYDROCORTISONE
FIG. 5. Relationship of THS excretion to cortisol synthesis.
THS excretions of this magnitude have been noted in two other conditions only, congenital adrenal hyperplasia with hypertension [24], and after treatment with Metopirone® [25].
In view of the often striking clinical manifesta- tions of adrenal cortical cancer, it is pertinent to ask why the diagnosis is usually made so late. One important factor is the inefficiency of steroid production by the neoplastic tissue. The normal adrenal produces enough cortisol so that 17-OHCS excretion levels average about 1 mg. per gm. of adrenal tissue. An adrenal adenoma may be so efficient in producing steroids that a 5 gm. adenoma may produce Cushing’s syndrome and an increase in 17-OHCS excretion. Adrenal carcinoma, however, has a characteristically low efficiency of steroid pro- duction which, in fact, ranges from zero in the nonfunctional cancer to perhaps as much as 0.1 to 0.2 mg. per gm. of tissue. Because of this factor, only when the cancer mass is large does steroid production reach higher than normal levels and clinical features of hormone excess appear. These estimates, based on our own experience, are subject to many uncertainties, particularly with respect to adrenal cancer, since necrotic and hemorrhagic tissue contribute to the weight of the cancer. Nevertheless, the conclusions about efficiency of steroid produc- tion should be qualitatively correct even if quantitatively uncertain.
Initial Therapy. In only eighteen patients was it possible to attempt curative cancer surgery. In the others, widespread local extension or distant metastases permitted only palliative resection or biopsy. In one patient in this series, a tissue diagnosis was not made before death. Five of the eighteen patients who underwent
! 3
No
NUMBER OF PATIENTS
Endocrine Syndrome
Endocrine Syndrome
12
Alive
11
+
10
9
-
8
7
€
5
4
+
3
+
2
+
+
I
+
+
+
U
i
2
3
4
5
6
7
8
9
SURVIVAL FROM ONSET OF SYMPTOMS (Years)
NO SURGERY OR BIOPSY ONLY
6
12
5
NUMBER OF PATIENTS
4
* Alive
3
2
1
0
ATTEMPT AT CURATIVE RESECTION
5
NUMBER OF PATIENTS
4
3
2
1
0
I
2
3
4
5
6
7
8
9
SURVIVAL FROM ONSET OF SYMPTOMS ( Years )
definitive cancer surgery received radiation therapy after surgery, 3,000 r. or more to the tumor bed. This did not seem to prevent the early appearance of metastatic disease.
Course of the Disease. Although on occasion adrenal cancer may progress slowly, it is generally a highly malignant tumor leading to death soon after the onset of symptoms (Fig. 6). Fifty per cent of the patients died within two years of the onset of symptoms. Only seven patients were alive more than five years after the onset of symptoms, and of these two were free of disease. In MacFarlane’s series, thirteen patients from a group of fifty-five survived for three years. If his figures are corrected by eliminating operative mortality, the three-year survival rate increases to 30 per cent. Since this is calculated from the time of surgery, it is appreciably higher than that observed in our series and may reflect patient selection.
A priori, one might expect that the diagnosis in patients in whom virilization or Cushing’s syndrome develops would be made earlier and therapy instituted sooner than in patients with- out endocrine syndromes, and that their chances for cure would thus be better. Our data do not support this expectation, but the bias in the series may be significant. MacFarlane also com- mented on the good survival rate of his group of patients with nonfunctional carcinoma. How- ever, in two other series of such patients [11,12] only two of thirteen patients with nonfunctional carcinoma survived more than three years.
Figure 7 shows the results of attempts at curative surgery on survival. Patients whose cancers precluded attempts at curative surgery
had a very limited life expectancy, over 70 per cent of the patients dying within two ycars. Thc one patient in this group who is still alive was treated with o,p’DDD; this case has been recorded [26]. The survival time in the operable group was longer. This does not necessarily imply that carly detection will improve survival time, since the operable group may be composed of patients in whom the tumor spread less rapidly.
Mode of Spread. Adrenal cancer metastasizes most frequently to the lungs and liver. It spreads locally and invades mesentery, omentum and kidney. It has a propensity to form large intra- abdominal tumors that may erode viscera or invade the large abdominal veins. Abdominal lymph nodes and mediastinal nodes are fre- quently involved. In only one instance were there skeletal metastases. Metastases have been seen in spleen, thyroid, ovary, scalp, pharyngeal tonsil and subcutaneous tissue. The brain has not been involved.
Cause of Death. The immediate causes of death are listed in Table v. Since it was difficult to dissociate the several terminal events resulting in death in several patients, more than one cause is given for somc. Septicemia was the most common cause of death, due to a gram-negative organism in each case. Foci of suppuration were
| Cause | No. |
|---|---|
| Septicemia | 7 |
| Hemorrhage | 4 |
| Large tumor masses, inanition and broncho- pneumonia | 7 |
| Thrombosis of inferior vena cava | 4 |
| Hepatic metastases | 2 |
| Pulmonary insufficiency | 1 |
| Pulmonary emboli | 2 |
| Renal failure | 1 |
| Unrelated | 2 |
| Unknown | 3 |
observed within necrotic tumor masses in several patients. Hemorrhage from necrotizing tumor was the direct cause of death in four patients. This is an expected finding in view of the high incidence of hemorrhage noted within tumor nodules. Death in six patients was related to the many large intra-abdominal masses that interfered with nutrition by pressure on the stomach or by displacing other parts of the gastrointestinal tract. The late occurrence of marked sodium retention, edema and its complications was caused by tumor thrombosis of the inferior vena cava in three patients. Despite the high incidence of hepatic metastases, death from hepatic failure was rare.
Morbid Anatomy. The primary tumor was not available for analysis in all cases; metastatic tumors were recovered at postmortem in most cases. Grossly, the metastases were fairly well circumscribed, whitish to grayish tan colored masses of friable tissue. The consistency of the tissue varied in accordance with the extent of necrosis. In the cut surface, primary tumors and metastatic deposits alike were grayish tan to yellow with mingled, scattered, dark red hemor- rhagic areas. (Fig. 8.)
Microscopically, the tumor tissue was cellular with anaplastic cells arranged in sheets, cords and, occasionally, nests. Invasion of the capsule by neoplastic cells was frequently noted. Masses of cells were interspersed with thin-walled vascular spaces. Areas of hemorrhage were common. Bands of fibrous connective tissue occasionally delineated pseudolobules. Large areas of necrotic tumor tissue in varying states of degeneration were noted both in tissue recovered at surgical biopsy and in tissue
AMERICAN JOURNAL OF MEDICINE
recovered at postmortem examination. In some areas necrotic tumor tissue had been virtually replaced by connective tissue; occasionally, calcification was observed.
Tumor cells varied in size and shape from spindle-shaped cells with scant cytoplasm in the less differentiated tumors (Fig. 9) to large polyhedral cells with abundant homogeneous, finely granular, eosinophilic cytoplasm in the more differentiated tumors. (Fig. 10.) Occa- sional cells with cytoplasm exhibiting the lightly- staining foamy qualities of cells of the fasciculata of the normal adrenal cortex were observed in the more differentiated tumors. Multinucleated giant cells were common.
Variations in the chromaticity and mor- phology of the nuclei usually associated with neoplasia were prominent features of both adenomas and carcinomas. Likewise, mitoses were common in both tumors. Lack of invasive- ness is one of the characteristics of adenomas and, conversely, the feature that is most sug- gestive of carcinoma is capsular invasion [27]. The differentiation of adenoma from carcinoma may be difficult on the basis of histologic features alone and therefore weight should be given to other considerations, such as tumor size and steroid excretion.
Lipid stains were not available for analysis. Superficial examination of sections stained with hematoxylin and eosin did not reveal any con- sistent differences between functioning and nonfunctioning tumors. A more detailed evalua- tion of the histopathology of these tumors is in progress.
VOL. 35, SEPTEMBER 1963
Treatment. The aim of treatment of adrenal cancer should be surgical removal of the tumor. MacFarlane has pointed out the correlations between survival and clinical staging of the disease. The finding of tumor cells in the renal vein need not necessarily mean failure, how- ever, since one of the long-term survivors in our group had microscopic invasion of the vein.
Surgery can be an effective mode of therapy in the palliation of adrenal cancer. Since, on occasion, there may be only a few large, discrete tumor masses in the abdomen, excision of these can lead to an appreciable decrease in local symptoms. When the tumor is responsible for florid virilization or Cushing’s syndrome, pallia- tive resection of one or more tumor masses may result in a temporary return to normal. Pallia- tive surgery cannot, of course, be used in most patients, but the occasional patient with a few discrete intra-abdominal metastases may be a suitable candidate.
This cancer has been observed to be radio- resistant and the small experience with radiation in this series suggests that this observation is correct. We have had no personal experience with radiotherapy, but general clinical experi- ence would not lead one to recommend it.
Since the recurrence rate of adrenocortical cancer is high, and since there is a partially effective form of therapy [28], it is important to follow the patient carefully after surgical resection. We would suggest that the urine levels of 17-KS and 17-OHCS be examined monthly if a functional cancer was removed. It seems possible that treatment with o,p’DDD
may be most successful in patients with the least disease. We would propose intensive therapy with o,p’DDD, despite its toxicity, as soon as an increasing urinary 17-KS excretion heralds the presence of metastatic disease. If less toxic derivatives of o,p’DDD become avail- able, it will be increasingly feasible to use them in the treatment of metastatic adrenal cancer.
SUMMARY
Adrenal cortical carcinoma is a highly malignant cancer that is usually diagnosed late in its course. The presenting complaints may be those due to the mass or those resulting from the secretion of large amounts of physiologically active steroids. Some of the distinctive features of adrenal cortical carcinoma are its large size at the time of diagnosis, the generally large amounts of steroids excreted in the urine when the tumor is functional, the increased excretion of dehydroepiandrosterone (DHEA) when 17- ketosteroid (17-KS) excretion is high, and the increased excretion of tetrahydro substance S (THS) when 17-hydroxycorticosteroid (17- OHCS) excretion is increased.
The rate of surgical cure is low. Following an attempt at resection of the carcinoma it is sug- gested that the excretion of steroids in the urine be examined at frequent intervals so that metastasis may be detected early and treatment initiated.
Acknowledgment: We sincerely thank the many physicians who have referred their patients to us for study and therapy.
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