ACTH Producing Matastases from Carcinoma of the Esophagus
FRANCIS N. LOHRENZ, M.D., and G. STANLEY CUSTER, M.D. Marshfield, Wisconsin
T HE ASSOCIATION of Cushing’s syndrome with “nonendocrine” tumors has been discussed in several recent reviews (1-3). The most fre- quent sites of primary tumor have been the lungs, thymus, or pancreas. Meador and asso- ciates (4) in 1962 demonstrated adrenocortico- tropin-like activity in five patients with hypo- kalemia, hypercorticism, and bilateral adrenal hyperplasia associated with neoplasms not of pituitary or adrenal origin. Adrenocorticotropic hormone (ACTH)-like material was present in the primary tumor, in metastatic tissue, and in the plasma of each patient. Liddle and asso- ciates (5) subsequently demonstrated active ACTH-like material in the primary and meta- static tumor of 13 patients. They suggested a change in terminology from “tumors of non- endocrine tissue” to “ectopic adrenocortico- tropin production by nonpituitary tumors.” In 1964, Hallwright, North, and Reid (6) reported a patient with Cushing’s syndrome due to a malignant tumor of the pancreas. Extracts of this tumor showed high levels of ACTH and melanocyte stimulating hormone MSH.
Cushing’s syndrome in association with gas- trointestinal tract malignancies other than the pancreas is rare. The previously reported cases are shown in Table 1.
This paper is the first report of a patient with carcinoma of the esophagus in which ACTH-like material was demonstrated in the hepatic metastases.
CASE REPORT
M. P., a 54-year-old white female, was admitted to the hospital on June 29, 1964. Her chief com-
Received November 9, 1964; accepted for publi- cation January 19, 1965.
From the Marshfield Clinic and Marshfield Clinic Foundation for Medical Research and Education, Marshfield, Wisc.
Requests for reprints should be addressed to Francis N. Lohrenz, M.D., Marshfield Clinic, 630 South Central Ave., Marshfield, Wisc. 54449.
plaint was weakness, puffiness, and dizziness of 4 weeks’ duration.
The patient had a previous admission from August 19 to September 6, 1960, with a diagnosis of Laennec’s cirrhosis with ascites. Alcohol intake from 1950 to 1960 had been considerable. She responded to a low sodium diet, bed rest, mercurial diuretics, and alcohol withdrawal. No liver biopsy was performed. She had no further symptoms until November, 1963, when she noted epigastric pain and vomiting. An oral cholecystogram was normal. An upper gastrointestinal (G.I.) series revealed a small sliding hiatus hernia with no evidence of ulcer or tumor.
On June 6, 1964, she noted puffiness about the face, eyes, abdomen, and legs. There was severe dyspnea. Several injections of mercurial diuretics resulted in some decrease of edema. She continued to feel weak and dizzy and complained of a full sensation in her abdomen. She had been increas- ingly slow in thought and speech for several months. Family history and social history were not contributory. She denied history of significant alco- hol intake for 4 years.
Physical examination revealed a well-developed, phlegmatic, mentally cloudy white female with generalized tanning of her skin. Her voice was weak. She weighed 140 pounds. The blood pressure was 148/80 mm Hg, and the pulse rate was 80/ min. The pupils were small, regular, and equal. They reacted sluggishly to light. Examination of the fundi showed the disk margins to be some- what blurred, and the veins were dilated. Early papilledema was present. There was a 2-cm lump palpable in the left anterior neck beneath the sternocleidomastoideole. There was a Grade II systolic precordial murmur. A large nodular and tender liver was palpable. It extended across the abdomen to 6 cm below the right costal margin. The spleen was not palpable. Pelvic examination showed no abnormalities. The deep tendon reflexes were active and equal in the upper extremities but could not be elicited in the lower extremities.
Laboratory examination showed a hemoglobin of 12.8 g/100 ml. The hematocrit reading was 38%. The WBC was 14,800/mm3 with 71% neutro- phils, 16% band cells, 8% lymphocytes, and 5% monocytes. On June 29, 1964, the total serum bilirubin was 1.4 mg/100 ml with the direct, 0.6 and the indirect, 0.8 mg/100 ml. On July 8, 1964, the total serum bilirubin was 5.4 mg/100 ml with the direct, 3.3 and the indirect, 2.1 mg/100 ml. The total proteins on admission were 6.2 g/100 ml.
| Author | Date Reported | Sex Age | Symptoms | Laboratory Data | Site and Relationship to Cushing's Syndrome | |
|---|---|---|---|---|---|---|
| 1. Warren (10) | 1944 | F 38 | Virilism, large abdominal tumor | Elevated 17-KS | Colon, splenic flexure, con- current | |
| 2. Poutasse and Higgins (12) | 1953 | - - | Clinical Cushing's syndrome re- sponding to testosterone treatment | - | Carcinoma of esophagus found 12 years after diagnosis of Cushing's syndrome | |
| 3. Brickner and associates (13) | 1960 | F 62 | Hirsute, "buffalo hump," ab- dominal pain | Elevated 17-KGS and 17-KS | Gallbladder, concurrent | |
| 4. Riggs and Sprague (2) | 1961 | F 58 | - | - | Adenocarcinoma in situ of colon (1} years before diagnosis of Cushing's syndrome) | |
| 5. Riggs and Sprague (2) | 1961 | F | 42 | - | - | Adenocarcinoma of colon found 12 years after diagnosis of Cushing's syndrome |
| 6. Matys and associates (14) | 1963 | F 46 | Clinical Cushing's syndrome | - | Adenocarcinoma of colon, con- current | |
The albumin was 3.4 g/100 ml, and the globulin was 2.8 g/100 ml. The alkaline phosphatase was 11.5 King-Armstrong units. A bromsulphalein test showed 40% retention of dye in 45 minutes. The cephalin flocculation test was 2+ at 24 and 48 hours. The total cholesterol was 177 mg/100 ml. Enzyme studies showed serum glutamic oxalo- acetic transaminase (SGOT), 196 units, serum glutamic pyruvic transaminase (SGPT), 91 units and lactic acid dehydrogenase (LDH), 3,850 units. Spinal tap yielded a clear fluid with normal pressures. The total protein in the spinal fluid was 69 mg/100 ml; glucose, 84 mg/100 ml; and the LDH, 83 units. The electrolyte studies demonstrating the severe hypokalemic alkalosis are shown in Table 2. The results of adrenocortical studies are shown in Table 3. The urinary elec- trolyte excretions are shown in Table 4. During the first 5 days of the patient’s hospitalization, mercurial diuretics by injection and oral hydro- chlorothiazide were administered in an attempt to decrease the edema. Oral and parenteral potassium was given to correct the severe hypokalemia. A left cervical node biopsy showed a poorly differ- entiated squamous cell carcinoma. X rays of the
chest during hospitalization showed marked hilar adenopathy. Because of the severity of her illness, suppression studies with dexamethasone, stimula- tion with ACTH, and SU-4885 (Metapirone®) tests could not be performed. The patient’s confu- sion increased. She died on July 9, 1964.
PATHOLOGICAL FINDINGS
An autopsy was performed. The body ap- peared icteric. The peritoneal cavity contained approximately 550 ml of straw-colored fluid. There were numerous whitish-gray nodules in the periaortic region measuring approximately 3 cm in length. There was a large reddish-yel- low nodule over the superior pole of the left kidney. The pleural cavities contained 150 ml of straw-colored fluid on the right and 200 ml on the left side. Other significant findings were those in the esophagus. Approximately 15 cm from the pharyngeal-esophageal junction, there was an infiltrating, raised, firm, whitish lesion
| Date 1964 | Serum Sodium | Serum Potassium | Chloride | pH | Bicarbonate | Pco2 | Base Excess* |
|---|---|---|---|---|---|---|---|
| m Eq/liter | mEq/liter | mm Hg | mEq/liter | ||||
| July 3 | 142 | 1.9 | 62 | 7.60 | 75 | 75 | +55 |
| July 6 | 130 | 2.45 | 71 | 7.66 | 51 | 46 | +33 |
| July 7 | 120 | 3.1 | 69 | 7.63 | 49 | 46 | +28 |
| July 8 | 135 | 3.05 | 78 | 7.58 | 38 | 42 | +18 |
* See Reference 15.
| Date 1964 | 24-hr. Urine Volume | Creatinine | 17-OHCS* | 17-KSt | Plasma 17-OHCSt |
|---|---|---|---|---|---|
| ml | g/24 hr | € mg/24 | hr * | pg/100 ml | |
| July 5 | 740 | 0.8 | 42.0 | 11.0 | 2:30 PM = 190.0 |
| July 6 | 650 | 0.65 | 31.0 | 10.9 | - |
| July 7 | 690 | 0.65 | 32.0 | 12.0 | 8:00 AM = 235.0 |
| 5:00 PM = 250.0 | |||||
| 9:00 PM = 260.0 |
* See reference 16.
t See reference 17.
# See reference 18.
6 cm in length. This tumor encircled all but 1 cm of the esophageal wall. Cut sections of the lesion revealed whitish-yellow, firm tissue that infiltrated the mucosa, muscularis, and serosa of the esophagus. The stomach, duode- num, and remainder of the gastrointestinal tract contained no lesions. The liver weighed 2,930 g. The surface was studded by numerous umbilicated, whitish-yellow nodules, between which residual brownish-yellow parenchyma was seen. Sixty per cent of the liver was in- vaded by yellowish-white, somewhat hemor- rhagic soft lesions. The pancreas was of normal size and shape. No lesions were found in the larynx, trachea, or bronchi. There were nu- merous firm nodules involved with tumor in the hilar areas of both lungs. The right adrenal gland was normal in size, shape, and position. The left adrenal gland was slightly enlarged and contained a reddish-white, somewhat firm, 3 cm nodule. The cut surface of the cortex was tan and the medulla was reddish-brown. The surface of both kidneys contained numerous raised yellowish nodules. There were many large matted aortic abdominal left cervical and hilar nodes. The largest measured 8 cm in diameter. The bone marrow appeared normal.
Histologic examination of the tumor (Figure 1) shows the typical findings of squamous cell
| Date 1964 | Sodium | Potassium | Chloride |
|---|---|---|---|
| € mEq/24 hr > | |||
| July 5 | 0 | 12 | 4 |
| July 6 | 0 | 25 | 2 |
| July 7 | 1 | 33 | 0 |
carcinoma of the esophagus with surrounding metastasis. The left adrenal shows normal tis- sue with invasion by squamous cell carcinoma (Figure 2). The right adrenal was normal. His- tologic examination of the liver (Figure 3) showed hepatic metastasis with marked involve- ment by squamous cell carcinoma. The pitui- tary was normal to gross inspection. Micro- scopic sections were not available for further study.
A portion of liver containing metastatic nodules was frozen immediately and bioassay
for ACTH was performed by Dr. Grant Liddle at Vanderbilt University. Demonstrated in the hepatic metastasis was 0.2 mU of ACTH/g of tissue. This is a significant level, particularly considering the large amount of such tissue present in this patient (5).
DISCUSSION
Hypokalemic alkalosis with Cushing’s syn- drome has been reported in 12 of 43 patients by Christy and Laragh (7). Seven cases in this group had bilateral adrenal hyperplasia, and three had associated “nonendocrine” neo- plasms. The remaining five had adrenal neo- plasms. These authors postulated that the po- tassium depletion and metabolic alkalosis of Cushing’s syndrome was due to the grossly exaggerated secretion of 17-hydroxycortico- steroids (17-OHCS) rather than the oversecre- tion of aldosterone. In our patient, the use of mercurial diuretics and hydrochlorothiazide probably helped to accentuate the hypokalemia. Because these patients do not always have the full clinical features of Cushing’s syndrome, the presence of a severe metabolic alkalosis should prompt evaluation of adrenocortical function. The high levels of plasma 17-OHCS would certainly confirm this diagnosis. Further- more, this patient also demonstrated the ab- sence of circadian variation in plasma 17- OHCS. This lack of circadian variation has been described by Doe, Vennes, and Flink (8) in five patients with Cushing’s syndrome due to bilateral adrenal hyperplasia. Allott and Skelton (1) described the association of Cush- ing’s syndrome with severe hypokalemia due to neoplasms of extra-adrenal origin. Bagshawe (9) emphasized that the severe hypokalemic alkalosis might be present for some time be- fore the diagnosis of a neoplasm from a “non- endocrine” source is made. In this patient, the symptoms of dizziness, weakness, and lethargy with the electrolyte and acid-base studies were consistent with severe hypokalemic alkalosis. Subsequent investigation of adrenal function revealed hypercorticism. This prompted the investigation of the hepatic metastasis for ACTH-like material.
The primary source of the tumor is of par- ticular interest. Warren (10) reported a woman with virilism, 17-ketosteroids of 80 mg/24 hrs, and abdominal swelling. No other laboratory
or clinical evidence of hypercorticism was re- corded. Autopsy showed a carcinoma of the colon. Her symptoms of Cushing’s syndrome occurred concurrently with the tumor. Hall- wright and associates (6) recently reported a 32-year-old Chinese woman with classic Cush- ing’s syndrome. She died with a tumor of the pancreas 2 years after a good remission with bilateral adrenalectomy. The cell type was of a carcinoid pattern with widespread metastasis. Extracts of the tumor gave a high assay for ACTH and MSH activity. Nichols, Warren, and Mantz (11) reported a case of Sertoli-cell carcinoma of the ovary with ACTH-like ma- terial extracted from metastatic tissue.
To our knowledge, the actual demonstra- tion of ACTH-like substance in tissue from metastatic or primary squamous cell carcinoma of the esophagus has not been previously re- ported. The data on this patient suggests that malignancies other than those described in the literature may be a source of ACTH-like ma- terial. The presence of a severe hypokalemic alkalosis in association with any malignancy should prompt a systematic investigation for hypercorticism due to ACTH-like activity in metastatic lesions.
SUMMARY
A 54-year-old female with severe hypokalemic alkalosis and squamous cell carcinoma of the esophagus is reported. Steroid studies verified hypercorticism. The hepatic metastases con- tained significant amounts of ACTH-like ma- terial.
ACKNOWLEDGMENTS
The authors are indebted to H. S. Waters, M.D., for referral of this patient.
The bioassay of ACTH of metastatic tissue was done through the courtesy of Grant Liddle, M.D., Vanderbilt University School of Medicine.
The pathological sections were reviewed by Robert Neubecker, M.D. of St. Joseph’s Hospital.
The authors also are indebted to Mr. Frederick J. Wenzel, Director of Laboratories, Marshfield Clinic, for performing the adrenal function stud- ies and for much help in preparation of the manu- script.
SUMMARIO IN INTERLINGUA
Isto es le prime caso reportate de un patiente in qui un substantia ACTH-simile esseva trovate in metastases hepatic ab un carcinoma
esophagee a cellulas squamose. Un sever al- calosis hypocaliemic urgeva le investigation del functionamento adrenal. Studios del steroides monstrava extrememente alte nivellos plasmatic de 17-hydroxycorticosteroide sin variation in parallela al cyclo diurne. Essayage del meta- stases hepatic demonstrava le presentia de un concentration significative de materiales ACTH- simile. Es revistate summarimente le previe- mente reportate casos de non-pancreatic neo- plasmas gastrointestinal associate con le syndrome de Cushing.
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