Small Cell Lung Carcinoma with Ectopic Adrenocorticotropic Hormone and Antidiuretic Hormone Syndromes: A Case Report
HIROKO SUZUKI, M.D.1) *. YUTAKA TSUTSUMI, M.D.2). KEN YAMAGUCHI, M.D.3), KAORU ABE, M.D.3) AND TAKESHI YOKOYAMA, M.D.1)
1) Department of Internal Medicine, Keiyu General Hospital. Yokohama, Japan
2) Department of Pathology, Tokai University School of Medicine. Isehara, Japan
3) Endocrinology Division, National Cancer Center Institute, Tokyo, Japan
Abstract
This report describes a 63-yr-old man with lung cancer accompanying hypertension, hyperpigmentation, muscle weakness, psychosis, hypokalemia, hyperglycemia, hyponatremia, massive naturesis and lower serum osmolality than urine osmolality. Elevated levels of plasma and urine corticosteroids and of plasma immunoreactive adrenocorticotropic hormone (ACTH) were not altered by the administration of large amounts of dexamethasone. Elevated plasma antidiuretic hormone (ADH) values were also demonstrated. Post- mortem examinations revealed small cell lung carcinoma with extensive metas- tasis, bilateral adrenocortical hyperplasia and Crooke’s degeneration of the pituitary gland. Immunoradiological and immunohistochemical studies demon- strated the presence of immunoreactive ACTH, ADH and gastrin-releasing peptide in the tumor tissue. Beta-melanocyte-stimulating hormone, calcitonin and carcinoembryonic antigen were also detected by one of the methods. Hence, this is a rare case of lung cancer with multiple hormone production and clinical and laboratory evidence of both the ectopic ACTH and ADH syndromes.
Received on January 24, 1984.
* Present address: Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Reprint requests: Hiroko Suzuki, M.D., Department of Internal Medicine, Keio Uni- versity School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160, Japan.
Abbreviations used in this paper are: ACTH, adrenocorticotropic hormone; ADH, anti-diuretic hormone: 3-MSH, beta-melano- cyte-stimulating hormone: GRP, gastrin-releas- ing peptide; CT, calcitonin; SS, somatostatin: VIP, vasoactive intestinal peptide: CEA, car- cinoembryonic antigen: RIA, radioimmuno- assay; 17-OHCS, 17-hydroxycorticosteroids; 17- KS, 17-ketosteroids.
Introduction
A variety of tumors, most commonly bronchogenic carcinoma, can secrete ectopic hormones (Gewirtz and Yallow, 1974; Yesner, 1978; Imura, 1980). Single tumors containing several hormones have been seen (O’Neal et al., 1968; Hirata et al., 1976;
This investigation was supported in part by Grants-in-Aid for Cancer Research (56-6, 56S-1, 57-8, 57S), Grants for Specific Diseases from the Ministry of Health and Welfare, and by Grants-in-Aid for Cancer Research from the Ministry of Education, Science and Cul- ture, Japan.
Abe et al., 1977), but tumors accompanied by clinical manifestations of each of two or more different ectopic hormones rarely occur (Cullen and Tomlinson, 1968; Costia et al., 1977; Ishikawa et al., 1980). In the present report, we describe a case of small cell lung carcinoma associated with both the ectopic adrenocorticotropic hormone (ACTH) and antidiuretic hormone (ADH) syndromes. Im- munoradiological and immunohistochemical characterizations of the tumor are presented.
Case Report
A 63-yr-old male was admitted on April 17, 1980, to Keiyu General Hospital with a 6-wk history of productive cough, back pain, dyspnea, anorexia, weight loss and weakness in both legs. He had smoked about 60 cigarettes per day for over 40 years. His father had died of gastric cancer.
He was slightly emaciated, emotionally labile, and had a dry tongue. The pulse rate was 96/min with regular rhythm and the blood pressure 200/100 mm Hg. Central obesity, buffalo hump, moon face, striae, ecchymoses and edema were absent, but there was slight generalized hyperpigmenta-
tion. Several large lymph nodes were palpa- ble in the right side of the neck. Moist rales and rhonchi were heard over the right upper chest. The edge of the liver was firm and felt three fingerbreadths below the right costal margin. Slight muscle weakness in both legs without sensory disturbance was noted. Deep tendon reflexes were normal.
Initial laboratory values included a hema- tocrit of 35% and a white blood cell count of 11,700/mm3 with 3% myelocytes, 2% metamyelocytes, 18% rods, 45% seg- mented forms, and 31% lymphocytes. The platelet count was 110,000/mm3 A few erythroblasts were present in a peripheral blood smear. The urine contained 4+ glucose but no protein or granular casts. The blood urea nitrogen was 25.4 mg/dl, serum creatinine 0.8 mg/dl, fasting blood sugar 189 mg/dl, sodium 126 mEq/l, potassium 3.3 mEq/l, chloride 80 mEq/l, and bicar- bonate 31 mEq/l. Urinary sodium excre- tion was 63 mEq/day when his serum sodi- um value was 125 mEq/l. Serum and uri- nary osmolalities were 257 and 585 mOsm/ kg H2O, respectively. Serum glutamic oxalo- acetic transaminase was 85 U/ml, glutamic pyruvic transaminase 54 U/I, lactic dehydro-
| Date | Sodium (mEq/1) [136-145]a) | Serum | Plasma | Urine | |
|---|---|---|---|---|---|
| Osmolality (mOsm/KgH,O) [278-305] | ADH (pg/ml) [less than 5] | Sodium (mEq/day) | Osmolality (mOsm/KgH;O) | ||
| 1980 April 25 | 124 | 257 | 585 | ||
| 26 | 8.7 | ||||
| 27 | 280 | 63 | 322 | ||
| 28 | 125 | ||||
| May 1 | 273 | 82 | 302 | ||
| 2 | 126 | ||||
| 6 | 117 | ||||
| 7 | 230 | 57 | 463 | ||
| 8 | 234 | 89 | 479 | ||
| 12 | 111 | ||||
| 19 | 135 | over 35 |
a) [ ]: Normal range.
genase 4,049 U/l, of which type 5 was elevated to 26.3%, and alkaline phosphatase 60.2 KAU/I, of which both bone and liver types were elevated. Normal values included serum cholesterol, bilirubin, calcium, phos- phorous, ammonium and thyroxin. The serum level of carcinoembryonic antigen (CEA) was 124 ng/ml (normal range: less than 7 ng/ml). The study of cerebrospinal fluid was unremarkable.
A chest X-ray film showed an abnormal shadow in the right upper lung field and widening of the mediastinum. Bronchofiber- scopic examination showed an obstruction of the right B, bronchus and stenosis of the right B. and B, bronchi by a mass. The diagnosis of small cell carcinoma of the lung was obtained from brushing specimens. Computerized tomography of the abdomen revealed multiple metastatic foci in the liver. Chemotherapy (Nimustine hydrochloride 150 mg) was started on the seventh hospital
day. The patient’s hypertension and hyper- glycemia could not be controlled despite the use of antihypertensive agents and insulin, and hypokalemia persisted in spite of intra- venous potassium supply. Intravenous water supply and oral water intake induced severe hyponatremia associated with an excessive sodium loss in the urine (Table 1). He be- came confused and delirious. Progressively severe pancytopenia due to metastasis of the tumor to the bone marrow and probably due to a side effect of the chemotherapy devel- oped. On the 42nd hospital day (May 28, 1980), he died of bleeding from the gastro- intestinal tract.
Postmortem Examinations
Autopsy revealed a primary tumor in the right upper lobe which obliterated the lumen of the B, bronchial branch and continuously infiltrated into the subpleural region, peri-
bronchial spaces in the B., and B, areas and into the right main bronchus. Metastases were found in the lungs, pleurae, liver, bone marrow, adrenals, pancreas, spleen, thyroid, and in the paratracheal, mediastinal, cervical and hepatic hilar lymph nodes. The tumor was composed of monotonous small cells with hyperchromatic nuclei and scant cyto- plasm in a ribbon- or sheet-like arrange- ment (Fig. 1). Electronmicroscopically, a few neuroendocrine granules, about 50-150 nm in diameter, were present in the cyto- plasm of the tumor cells (Fig. 2), but the argyrophil reaction after Grimelius was nega- tive. Neither glandular nor squamous com- ponents were noted in the tumor. The his- tological diagnosis was small cell carcinoma of the oat cell type.
The adrenals were hyperplastic and weighed 13.4 g (left) and 7.9 g (right). The disproportionate weight of the left adrenal
was due to the presence of large metastatic foci and a myelolipoma. The zona fasciculata cells were enlarged, acidophilic and depleted of lipid (Fig. 3). The pituitary gland weighed 0.65 g and had a slight to moderate degree of Crooke’s hyaline degeneration in the basophilic cells but no adenomatous lesions (Fig. 3, inset). No pathologic findings were noted in Langerhans’ islets of the pancreas or in glomeruli of the kidney. Acute gastro- duodenal ulcers with evidence of recent bleeding were found.
Endocrine Studies
Urinary 17-hydroxycorticosteroids (17- OHCS) excretion ranged from 16.8 to 24.7 mg/day (normal range: 1.6-6.7 mg/day), and urinary 17-ketosteroids (17-KS) excre- tion ranged from 12.5 to 17.9 mg/day (nor- mal range: 2.6-7.6 mg/day). Serum cortisol
| Date | Dexamethasone (mg/day) | Urine | Serum | Plasma | ||
|---|---|---|---|---|---|---|
| 17-OHCS (mg/day) [1.6-6.7]a) | 17-KS (mg/day) [2 6-7.6] | Cortisol (ng/ml) [62.6-150.6] | ACTH (pg/ml) [10-90] | |||
| 1980 May | 6 | - | 12.6 | 8.6 | 365 | 50 |
| 7 | 2 | 20.4 | 5.0 | 440 | - | |
| 8 | 2 | 19.2 | 13.3 | 470 | 94 | |
| 9 | 8 | 12.6 | 10.9 | - | 50 | |
| 10 | 8 | 12.7 | 11.7 | 330 | 115 | |
a) [ ]: Normal range.
levels ranged from 330 to 470 ng/ml (nor- mal range: 62.5-150.6 ng/ml) and plasma ACTH levels were from 50 to 205 pg/ml (normal range: 10-90 pg/ml). Eight milli- grams of dexamethasone failed to suppress
the levels of serum cortisol, urinary 17- OHCS and plasma ACTH (Table 2). Sodi- um levels and osmolality in the serum and urine are summarized in Table 1. Plasma arginine-vasopressin (“ADH”) levels, deter-
mined by radioimmunoassay (RIA) after Kimura et al. (1980), were inappropriately elevated for the low serum osmolality (Table 1).
The metastatic tumor tissue in a para- tracheal lymph node obtained at autopsy was frozen and stored at -20℃ until ex- traction. A part of the tissue (about 2.0 g) was extracted by immersion in boiling water and then in 0.5 N acetic acid as described previously (Abe et al., 1977; Yamaguchi et al., 1980; Yanaihara et al., 1981). The amounts of ACTH, B-melanocyte-stimulating hormone (B-MSH), gastrin-releasing peptide (GRP), vasoactive intestinal polypeptide
(VIP), calcitonin (CT) and somatostatin (SS) were determined with respective RIA systems. Another part of the tissue (about 2.0 g) was extracted with acid acetone and assayed for ADH by RIA (Kimura et al., 1980). Results are given in Table 3, in which limits of detectability in the respective assays are also shown. Significant amounts of ADH, ACTH, B-MSH, GRP and CT were detected in the tumor extract.
Immunohistochemical Studies
The indirect immunoperoxidase method after Nakane (1975) was applied to forma-
4a
4b
4c
4d
| ADHa) | ACTH | B-MSH | GRP | CT | VIP | SS | |
|---|---|---|---|---|---|---|---|
| Hormone content (ng/g wet wt) | 90 | 6.1 | 3.6 | 48 | 5 | U.D.b) | - U.D. |
| Detectability (ng/g wet wt) | 0.1 | 2.5 - | 0.8 | 2.5 | 0.8 | 2.0 | 1.0 |
a) See text for abbreviations.
b) U.D .: Undetectable.
lin-fixed paraffin-embedded sections of a metastatic lesion in the liver. Antigens ex- amined for were: CEA, ACTH, ADH, CT, SS, glucagon, glicentin, pancreatic poly- peptide, gastrin, cholecystokinin, methionine- enkephalin, GRP, neurotensin, motilin, se- cretin, substance P and VIP. Antiserum against CEA (DAKO Immunoglobulins, Denmark) was previously absorbed with a perchloric-acid-extract of the spleen. Anti- serum against arginine-vasopressin was ob- tained from Calbiochem-Behring Co., USA. Anti-glucagon 19-29 (GC-5) and anti-SS (OAL-272) sera were purchased from Japan Immunoresearch Laboratories, Japan. Anti- human CT serum was obtained from Im- mulok, Inc., USA. Anti-methionine-enke- phalin serum was purchased from UCB Bioproducts, Belgium. Anti-ACTH 1-39 serum was produced in a rabbit by immuni- zation with synthetic human ACTH. Anti- bovine pancreatic polypeptide serum was a gift from Dr. R. E. Chance, Lilly Research Laboratories, USA. The other antisera against gut-type hormones were gifts from Dr. C. Yanaihara, Shizuoka College of Phar- macy, Shizuoka, Japan. These included anti- porcine glicentin 49-69 (R-4804), anti-hu- man little gastrin (GP-1304), anti-cholecy- stokinin 1-27 (R-5905), anti-porcine GRP (R-6903), anti-neurotensin (R-3511), anti- porcine motilin (R-1104), anti-porcine se- cretin (R-801), anti-substance P (R-2404) and anti-porcine VIP (R-502) antisera.
A few neoplastic cells were positive with the immunostaining for ACTH, ADH or GRP (Fig. 4a-c), while the other peptide hormones failed to be detected. In addition,
most of the tumor cells were strongly posi- tive for CEA (Fig. 4d).
Discussion
Clinical, hormonal, immunodiagnostic and pathological evaluations documented that our patient had a multiple hormone-pro- ducing small cell carcinoma of the lung.
He showed several features of the ectopic ACTH syndrome: hyperpigmentation, mus- cle weakness, hypertension, psychosis, hypo- kalemia and hyperglycemia. The hyper- adrenocorticism failed to be suppressed by the administration of a large amount of dexamethasone. Bilateral adrenocortical hy- perplasia and Crooke’s hyaline degeneration in the pituitary basophilic cells were com- patible with features of hyperadrenocorticism due to ectopic ACTH overproduction. Final- ly, ACTH was detected in the tumor tissue by both immunoradiological and immuno- histochemical techniques.
The patient also had features of the syndrome of inappropriate ADH secretion: hyponatremia, excessive renal sodium loss, absence of clinical evidence of volume deple- tion (except for a slightly dehydrated state at the time of admission), inappropriately concentrated urine, normal renal function, and no evidence of adrenal insufficiency or hypothyroidism. His plasma ADH levels were inappropriately high for the low serum osmolality. ADH immunoreactivity was also demonstrated in the tumor tissue immuno- radiologically and immunohistochemically.
In general, clinical manifestations due to ectopically produced hormones are fairly
rare, whereas detectable values of various hormones have been very frequently recorded in plasma of patients with cancer and in the cancer tissues (Gewirtz and Yallow, 1974; Yesner, 1978; Imura, 1980). Immunoreac- tive ACTH was found in almost all tissue extracts of lung cancer from patients without clinical evidence of Cushing’s syndrome, and over half of the patients with lung cancer had elevated plasma ACTH levels (Gewirtz and Yallow, 1974). In these cases, the predominant form of ACTH was big ACTH with a low biological activity (Gewirtz and Yallow, 1974). It has also been thought that the tumors synthesizing ACTH do not release it at a rate sufficient to cause hyper- adrenocorticism clinically (Imura et al., 1975), and that the clinical course of lung cancer, especially small cell carcinoma, is too rapid to accompany the typical features of Cushing’s syndrome (Imura, 1980). The simultaneous detection of multiple hormones in a single tumor, especially in small cell lung carcinoma, has been fairly frequently reported (O’Neal et al., 1968; Hirata et al., 1976; Abe et al., 1977); the combination of ACTH and ADH seems to be the most popular one. In fact, several cases with clini- cal and laboratory evidence of the simultane- ous production of ACTH and ADH have been reported. However, there are only three cases in which the presence of these two hormones was demonstrated in the tumor extracts (Cullen and Tomlinson, 1968; Costia et al., 1977; Ishikawa et al., 1980), and none of the previous reports have de- scribed the immunohistochemical approach.
Several recent studies suggested the pres- ence of immunoreactive bombesin in fetal lungs and primary lung tumors (Wharton et al., 1978; Moody et al., 1981). We have demonstrated that immunoreactive bombesin found in fetal lungs and primary lung tu- mors has an amino acid sequence similar to that of bombesin, and that this peptide is frequently produced by small cell carcinoma of the lung (Tsutsumi et al., 1983; Yama- guchi et al., 1983). In the present case, in
addition to ACTH and ADH, immunoreac- tive GRP was demonstrated in the tumor tissue by both the immunoradiological and immunohistochemical methods.
It is also worthy of note that most of the patient’s tumor cells, even those that were negative for peptide hormones, showed CEA, associated with a high serum CEA level. It is well known that CEA is the product of cancer cells of the colon, stomach and breast (Primus et al., 1981). It has also been re- ported that non-small cell lung cancers fre- quently exhibit CEA (Primus et al., 1981). The fact that the tumor cells of this case diffusely expressed CEA as well as several peptide hormones suggests that the tumor has the ability to differentiate into both endocrine and non-endocrine components (Yesner, 1978). However, CEA is also known to be a good marker for medullary carcinoma of the thyroid (DeLellis et al., 1978) which is another well-characterized neoplasm with endocrine nature. Therefore, it is possible that the cancer cells in this case show a phenotypic expression of CEA simi- lar to that in medullary thyroid carcinoma.
Acknowledgments
The authors are greatly indebted to Prof. William R. Brown, Gastroenterology Section, Veterans Administration Medical Center, Uni- versity of Colorado Health Sciences Center, Denver, for his kind efforts in reviewing this paper. Skillful measurements of serum and tissue immunoreactive ADH by Dr. Tokihisa Kimura, The 2nd Department of Internal Medicine, Tohoku University School of Medi- cine, Sendai, Japan, are also acknowledged.
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