Steroid hormone abnormalities in patients with carcinoma of the lung
J. Judson McNamara, M.D. (by invitation), Harold H. Varon, M.D. (by invitation), Donald L. Paulson, M.D., Indira Shah, M.D. (by invitation), and Harold C.
Urschel, Jr., M.D., Dallas, Texas
A variety of endocrine and metabolic abnormalities have been observed clinically in patients with carcinoma of the lung. Several of the most common of these are associated with an excess production of one or more of the steroid hormones. The most overt example is seen in patients with Cush- ing’s syndrome and lung cancer, usually but not invariably an oat cell carcinoma.1-3 Production of an adrenocorticotrophic hor- mone by the tumor has been shown to be the cause of the associated clinical endo- crine abnormality.4-8 Similar studies of lung cancer patients with hypertrophic pulmonary osteoarthropathy and gynecomastia have recently revealed excessive estrogen excre- tion which has been correlated with gonado- tropin production by the tumor.9, 10
Much of the existing literature is con- cerned with isolated patients in whom lung cancers are accompanied by clinically ap- parent endocrine disease. Since certain tu- mors are associated with conspicuous mani- festations of endocrine abnormalities it has seemed reasonable to study steroid hor- mones in a large number of patients with
From the Departments of Thoracic and Cardiovascular Surgery and Endocrinology, Baylor University Medical Center, Dallas, Texas.
Aided in part by a grant from Ayerst Laroratories, New York, N. Y.
Read at the Forty-eighth Annual Meeting of The American Association for Thoracic Surgery, Pittsburgh, Pa., April 22-24, 1968.
lung cancer but with no clinically apparent endocrine disease imbalance. The present study was designed to investigate plasma cortisol levels, response to ACTH, urinary 17-hydroxycorticosteroid and 17-ketosteroid excretion, and estrogen excretion in a series of patients with proved bronchogenic carci- noma in comparison with a control series of patients having benign disease.
Materials and methods
The study was conducted in three phases and included all patients admitted with a diagnosis of carcinoma of the lung. Patients were studied preoperatively and only those without a positive biopsy for bronchogenic carcinoma were excluded from the series. A total of 69 patients with carcinoma were studied, 60 men and 9 women. Control groups included 35 patients, 22 men and 13 women. Average age for both carcinoma and control patients was 62.3 years; the range for controls was 50 to 75 years and for those with carcinoma was 50 to 80 years. The control series consisted entirely of preoperative patients who subsequently underwent diaphragmatic hernia repair. Pa- tients under 50 years of age in both the carcinoma and control groups were not in- cluded in the study.
All carcinoma and control patients re- ceived the same screening process. Patients were excluded who had histories of radia-
tion or hormone therapy, other cancer, previous endocrine gland surgery, thyroid disease, cerebrovascular disease, recent myocardial infarction or current evidence of liver or kidney disease, abnormal urinalysis or abnormal blood chemistry values for blood urea nitrogen, creatinine, albumin, globulin, alkaline phosphatase, or 5-nucleo- tidase.
All studies were performed in the hospi- tal. Data recorded for each carcinoma pa- tient included cell type, stage of disease, and duration of survival after diagnosis. Tumors were classified into three groups: epidermoid carcinoma, adenocarcinoma, and small cell undifferentiated (oat cell) carcinoma. Tumors classified as large cell undifferentiated were included with the epi- dermoid group.
Criterion for staging the disease was based on the extent of the lesion. Stage I indicated localization to the lung or hilum (without mediastinal nodes), Stage II indi- cated carcinoma apparently limited to the thoracic cavity, and Stage III indicated ob- vious distant metastases.
The first phase of the study included a single 8:00 A.M. cortisol determination and a 24-hour urine collection for 17-hydroxy- corticosteroid (17-OH-CS) as Porter-Silber chromagen and 17-ketosteroid (17-KS) (10 patients).
The second phase included the above base line values followed by an ACTH test performed with a single injection of ACTH gel, 40 units, immediately after obtaining the 8:00 A.M. cortisol sample. A 12 M plasma cortisol and 24-hour urine collection for 17-OH-CS and 17-KS was then ob- tained. Normal range in our laboratory con- sists of a rise in plasma cortisol and urinary 17-OH-CS between 50 to 300 per cent above base line values (28 patients).
The third phase of the study included 24-hour urinary 17-OH-CS, 17-KS and total estrogen determinations as well as plasma cortisols drawn at 8:00 A.M., 4:00 P.M. and 10:00 P.M. on the day of the urine collections. The total estrogen was estimated from adding estrone, estradiol,
and estriol fractions. This phase of the study was designed to continue the screen- ing of plasma cortisol, 17-OH-CS, and 17- KS excretion and, in addition, included stud- ies to supply information on estrogen ex- cretion and the corticosteroid circadian rhythm (31 patients).
Control patients were studied in similar manner with 8:00 A.M. plasma cortisol (35 patients), 24-hour urinary 17-OH-CS and 17-KS excretion (30 patients), 24-hour urinary estrogen excretion (28 patients), 4:00 P.M. and 10:00 P.M. plasma cortisol determinations (25 patients).
The laboratory methods employed for all the above determinations are described in detail elsewhere.11-15
Results
Comparison of data on hormone determi- nations requires division of the carcinoma groups by sex. The groups are further di- vided on the basis of cell type. Statistical comparisons are made between individual groups by a standard test for the differences of two means.16
Men with lung cancer-controls. Men with epidermoid carcinomas had the most significant hormone abnormalities (Table I). Twenty-four hour excretion of 17-OH- CS was significantly greater than control values (P < 0.001). Although 8:00 A.M. cortisol values were not significantly ele- vated (P > 0.1), 4:00 P.M. and 10:00 P.M. values were significantly higher than control levels (P < 0.01 and 0.05, respec- tively), indicating a loss of the normal circadian rhythm.
ACTH testing of men with epidermoid carcinoma showed a greater than twofold increase in plasma cortisol and a threefold increase in 17-OH-CS excretion (Table II). This represents borderline hyperresponsive- ness to ACTH in this laboratory, although the insensitivity of the test makes this of marginal significance.
Men with epidermoid carcinoma excreted significantly more estrogen per 24 hours than control patients (P < 0.005). The in- crease was apparent in all fractions but was
| Control | Epidermoid ca. | Oat cell ca. | |
|---|---|---|---|
| 17-OH-CS excretion (mg./24 hr.) | 5.1 (17) | 8.8 (52)* | 7.9 (8) |
| 17-KS excretion (mg./24 hr.) | 6.8 (17) | 7.4 (52) | 7.8 (8) |
| Plasma cortisol (mcg. % ) | |||
| 8:00 A.M. | 17.4 (22) | 19.1 (52) | 21.6 (8) |
| 4:00 P.M. | 8.7 (12) | 13.7 (23)} | 11.1 (4) |
| 10:00 P.M. | 7.6 (12) | 12.1 (23)} | 9.0 (4) |
| Estrogen excretion (mcg./24 hr.) | |||
| Total estrogen | 5.8 (15) | 11.2 (21)§ | 7.5 (3) |
| Estrone | 2.0 | 3.1 | 2.0 |
| Estradiol | 1.4 | 2.9 | 3.3 |
| Estriol | 2.5 | 5.3| | 2.2 |
Legend: Numbers in parentheses indicate number of patients studied. Bold face type indicates P values 0.05 when com- pared with controls.
*P < 0.001 for 64 D.F.
*P < 0.025 for 35 D.F.
ĮP < 0.05 for 33 D.F.
§P < 0.005 for 35 D.F. |P < 0.005 for 32 D.F.
| Pre ACTH | Post ACTH | |||||
|---|---|---|---|---|---|---|
| 17-OH-CS (mg./24 hr.) | 17-KS (mg./24 hr.) | Cortisol (mcg. %) | 17-OH-CS (mg./24 hr.) | 17-KS (mg./24 hr.) | Cortisol (mcg. %) | |
| Epidermoid carcinoma (24) * | 6.3 | 7.2 | 22.6 | 23.9 | 9.1 | 45.8 |
| Small cell carcinoma (4)* | 8.4 | 9.7 | 29.0 | 9.1 | 31.6 | 59.0 |
*Numbers in parentheses indicate number of patients studied.
only significantly elevated in the estriol fraction (P < 0.005).
None of the data for men with oat cell carcinoma was significantly different from control values (P > 0.1 for all compari- sons) which may be due to the small sample size.
Women with lung cancer-controls. Women with epidermoid carcinoma appeared to have elevations of urinary estrogen and loss of circadian rhythm similar to that seen in the men; however, this difference was not significant (P > 0.1). Again, the small size of the groups involved obviated valid statistical comparison and the data are presented principally for completeness. Similarly, hormone values for oat cell carci-
nomas and adenocarcinomas in women did not differ significantly from control values (Table III).
No correlation was found between any of the hormone values in any of the carcinoma groups and the clinical stage of the disease. Since nearly half the patients were followed less than a year from first being studied, no correlation was found between the duration of survival and any of the observed hor- mone abnormalities.
Discussion
Comparing carcinoma with control groups, the data from the present study in- dicate significant abnormalities in the pro- duction and excretion of certain steroid
| Control | Epidermoid ca. | Oat cell ca. | Adenocarcinoma | |
|---|---|---|---|---|
| 17-OH-CS excretion (mg./24 hr.) | 5.6 (13)t | 5.7 (3) | 3.2 (1) | 5.4 (5) |
| 17-KS excretion (mg./24 hr.) | 4.6 | 5.5 | 1.3 | 6.6 |
| Plasma cortisol (mcg. %) | ||||
| 8:00 A.M. | 15.4 (13) | 10.5 (3) | 15.2 (1) | 14.4 (5) |
| 4:00 P.M. | 9.6 | 10.8 | 13.2 | 19.5 |
| 10:00 P.M. | 9.1 | 8.8 | 8.0 | 10.1 |
| Estrogen excretion (mcg./ | ||||
| 24 hr.) | ||||
| Total estrogen | 3.8 (13) | 6.6 (3) | 1.1 (1) | 6.6 (3) |
| Estrone | 1.3 | 2.4 | 0 | 2.4 |
| Estradiol | 0.9 | 1.5 | 1.1 | 1.5 |
| Estriol | 1.3 | 2.8 | 0 | 2.8 |
*P values for all carcinoma groups were > 0.05 when compared with controls.
+Numbers in parentheses indicate number of patients studied.
hormones in male patients with epidermoid carcinoma of the lung in the absence of clinical evidence of endocrine disease.
Significant increase in 17-OH-CS excre- tion was observed. Although morning plas- ma cortisol determinations were not signif- icantly elevated, significant elevation was found in plasma cortisol levels at 4:00 P.M. and 10:00 P.M. This indicates a loss of the normal circadian rhythm17 due to sustained steroidogenesis and is consistent with earlier work by Sholiton18 and Hymes.19
A number of previous studies support these observations and implicate the adrenal gland as the source of this increased pro- duction of corticosteroids. Adrenocortical hyperplasia has been found in postmortem examination of patients dying from lung cancer.1, 20-25 Adrenal hyperresponsiveness to ACTH has been demonstrated in the absence of clinical Cushing’s syndrome19, 20, 26, 27 and is suggestively supported by data from the present study. Elevation of 17- OH-CS excretion and increased plasma cor- tisol levels have also been previously ob- served.19, 26, 28 The latter findings have not been uniformly consistent, possibly due to
failure to subdivide the patients on the basis of cell type. Marmorston29 has demon- strated similar abnormalities in the hormone excretion pattern in patients with squamous cell and adenocarcinoma which differ sig- nificantly from that observed in patients with oat cell tumors.
The reason for the apparent increased corticosteroid production by the adrenal is not clear. Belsky and Marks26 after de- tecting corticotropin activity in the pituitary of 7 patients dying of lung cancer without clinical endocrine disease, suggested that it was due to an effect of chronic and severe illness on pituitary-adrenal function and not specific for lung cancer. On the other hand, certain lung carcinomas have been shown to produce corticotropin, biologically and chemically similar to ACTH, in sufficient amounts to cause severe Cushing’s syn- drome.4-8, 30 This has usually occurred in patients with oat cell carcinomas1-8, 30-3+ al- though it has now been seen with well- differentiated carcinomas20, 29 and bronchial adenomas as well.21, 35-37
Since isolated documented instances of massive corticotropin production by certain lung cancers are now known, production of
subclinical amounts of corticotropin by many lung cancers may occur commonly and explain the observed chemical abnor- malities in corticosteroid hormone produc- tion in patients with lung cancer but no clinically obvious endocrine disease. The fact remains that the observed hormone abnormalities are real and an explanation requires more study, particularly directed at determining plasma and tumor cortico- tropin activity in a large group of patients with lung cancer.
Examination of estrogen data from the present study indicates a significant eleva- tion of total estrogen excretion by men with epidermoid carcinoma when compared with male controls. Similarly, the estriol fraction was significantly elevated. Values were low- er for oat cell carcinoma, although the group was small.
Previous postmortem studies of endocrine organs and their target organs in patients dying with lung cancer without clinical en- docrine disease demonstrate evidence of estrogen excess in adenocarcinoma and epi- dermoid carcinoma but low estrogen pro- duction with oat cell carcinoma.24, 25 Cole 38 found elevated total estrogen excretion in 4 of 8 patients studied with carcinoma of the lung and no clinical manifestations of endocrine disease.39 Marmorston studied 55 patients with lung cancer and found total estrogen excretion highest in patients with adenocarcinoma and lowest in those with oat cell carcinoma.
The first observations of excess estrogen excretion in patients with lung cancer were noted in carcinoma patients with gyneco- mastia and hypertrophic pulmonary osteo- arthropathy.40, 41 It was also noted that with treatment of the tumor by resection or ir- radiation, estrogen excretion would fall and osteoarthropathy and gynecomastia would disappear.42
This situation may be analogous to that observed with abnormalities in adrenocor- ticosteroids and lung cancer in which a few patients with lung cancer have overt clinical manifestations of abnormal hormone pro- duction yet the majority of patients exhibit
abnormal steroid hormone patterns in the absence of clinically apparent endocrine imbalance.
Recently, two studies have demonstrated gonadotropin production by the tumor in 5 patients with gynecomastia, elevated uri- nary estrogen excretion, and carcinoma of the lung.9, 10 The tumors were all histo- logically similar and were diagnosed as large cell undifferentiated carcinoma. Here again, since some conspicuous cases of clinical “hyperestrogenism” and lung cancer now are proved to be due to gonadotropin pro- duction by the tumor, many other carci- nomas may produce subclinical amounts of gonadotropin. This would account for the observed elevation in estrogen excretion in a group of patients, such as the present study, with cancer of the lung and no overt endocrine disorder. Further studies on go- nadotropin activity in a large group of un- selected carcinoma patients are needed to define this relationship.
Ketosteroids in the present study were normal in carcinoma patients and this has been a consistent finding.20, 30, 43 Little evi- dence of significant abnormality of testos- terone or progesterone metabolism in pa- tients with lung cancer has been reported.43
Plasma 17-hydroxycorticoid hyperrespon- siveness has previously been related to de- creased survival28 and exogenous cortisone administration has been associated with shortened survival.44 The present study did not demonstrate any relationship between life expectancy and steroid hormone pro- duction although follow-up has been too short to adequately evaluate this relation- ship.
It is intriguing that lung tumor cortico- tropin production resulting in clinical Cush- ing’s syndrome occurs predominantly with anaplastic oat cell carcinomas whereas demonstrated gonadotropin production has occurred predominantly with undifferenti- ated large cell carcinoma. One might hy- pothesize that the structural similarity of corticotropic and gonadotropic hormones allow for production of both by similar cells and that one or more of the factors responsi-
ble for the histologic differentiation into large cell or small cell tumors also deter- mine the principal hormone synthesis po- tential of the cell. The well-differentiated squamous cancers, lying someplace in be- tween, may have less propensity to massive hormone production but retain the ability to secrete lesser amounts of either type.
The possible significance of hormone ab- normalities in patients with lung cancer with respect to diagnosis, prognosis, treatment or tumor behavior or pathogenesis remains obscure. The latter has received some in- teresting hypothetical consideration in the literature.19, 24, 29
Summary
Steroid hormone levels were measured in the blood and urine of 69 patients with carcinoma of the lung with the following findings:
1. Men with epidermoid carcinoma ex- crete abnormally large amounts of 17-hy- droxycorticosteroid in the urine.
2. They also have normal 8:00 A.M. plas- ma cortisol levels, but 4:00 P.M. and 10:00 P.M. levels are elevated which indicates a loss of normal corticosteroid circadian rhythm.
3. ACTH testing suggests adrenal hyper- responsiveness in men with epidermoid car- cinoma.
4. Men with epidermoid carcinoma ex- crete excess quantities of total urinary estro- gen, the majority of which is accounted for by an excess excretion of estriol.
5. Significant abnormalities were not found in other carcinoma cell types in men or in any of the carcinomas in women. The sample size in each instance, however, was small.
The current data are discussed in rela- tion to that previously reported in the litera- ture.
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