CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
Weekly Clinicopathological Exercises
FOUNDED BY RICHARD C. CABOT
BENJAMIN CASTLEMAN, M.D., Editor BETTY U. MCNEELY, Assistant Editor
CASE 17-1969 PRESENTATION OF CASE
A sixty-seven-year-old man was admitted to the hospital because of edema of the legs.
One year previously he was admitted to another hospital after a seizure; pneumonia developed, with a slow recovery. Nine months before admission an- kle edema occurred, and digitalis and chlorthali- done (Hygroton) were begun and continued to the time of entry. Because of weakness of the legs he remained in bed and chair in a nursing home dur- ing the next six months. Three months before entry the edema of the legs subsided, and he returned home, where he was ambulatory and able to care for himself. Two weeks before admission weakness and anorexia occurred, and the legs became edema- tous. Despite the injection of diuretics every other day the edema and weakness persisted.
He had drunk whiskey and beer in large amounts since the age of twenty years; during the nine months before admission he had ingested no alco- hol. He had sustained several injuries but had expe- rienced no gastrointestinal pain, bleeding, ascites or episodes of confusion.
On physical examination telangiectases were ob- served over the upper portion of the chest, and there was palmar erythema; no spider angiomas were present. The eyes, ears, nose and throat were normal. The neck was supple, and the cervical veins were flat; the thyroid gland was not enlarged. No lymph nodes were palpable. A few rales were audible anteriorly at the left-lung base, and the breath sounds were decreased. The point of maxi- mum cardiac impulse was within the mid-clavicular line; the heart sounds were soft; there was a Grade 2 apical systolic murmur that was poorly transmitted to the axilla; no gallop or rub was heard. The abdo- men was bulging, with slight shifting dullness; the edge of the liver, which was firm and questionably nodular, was felt 10 cm below the right costal mar-
gin, and the edge of the spleen was firm and was palpable 9 cm below the left costal margin; no fric- tion rub or bruit was heard. The testes were atroph- ic. Rectal examination was negative. There was ++++ edema of the lower extremities to the knees, with + edema to the iliac crests; no clubbing or cyanosis of the extremities or tenderness of the calves was found. The patient was not well oriented and performed tests of cerebral function poorly. Examination of the cranial nerves was negative. There was generalized weakness of the extremities, without alteration in tone; asterixis was not observed; the tendon reflexes were equivocal at the triceps and knees and absent at the wrists and ankles; the plan- tar responses were flexor; perception of sensory stimuli was reduced in the lower extremities.
The temperature was 99.4ºF, the respirations 26, and the pulse 84. The blood pressure was 150 sys- tolic, 60 diastolic.
The urine had a specific gravity of 1.017 and gave a trace-positive test for protein and a positive test for bile; the pH was 6.5; the sediment contained 10 white cells per high-power field. The hematocrit was 36 per cent, and the white-cell count 23,700, with 88 per cent neutrophils; the erythrocyte sedi- mentation rate was 18 mm per hour. The glucose was 88 mg, the urea nitrogen 28 mg, the bilirubin 4.0 mg, the calcium 7.2 mg, the phosphorus 2.4 mg, and the protein 5.3 gm (the albumin 3.7 gm, and the globulin 1.6 gm); the ammonia was 150 ug, the iron 109 µg, and the iron-binding capacity 289 ug per 100 ml. The sodium was 141 mEq, the potas- sium 1.9 mEq, the chloride 84 mEq, and the carbon dioxide 48 mEq per liter. The glutamic oxalacetic transaminase (SGOT) was 169 units, and the alka- line phosphatase 20.3 Bodansky units. The pro- thrombin time was 14.9 seconds, with a control of 12.2 seconds. An electrocardiogram (Fig. 1) revealed
0
AN
1
2
3
AVR
AVL
AVF
n
V1
V2
V3
V4
V5
V6
a sinus rhythm with an axis of -15°; there were T- wave inversions in Leads V, through Ve and low T waves in the standard leads. An x-ray film of the chest (Fig. 2) demonstrated several healed left-rib fractures, with adjacent pleural thickening; a few patchy infiltrates were evident at the lung bases; the size of the heart was at the upper limit of nor- mal, with slight left ventricular prominence. A lim- ited skull series was normal.
A low-sodium diet was given, and 25 per cent potassium chloride elixir, 5 ml three times daily, magnesium citrate and neomycin were instituted. On the second hospital day asterixis developed. The sodium was 145 mEq, the potassium 2.6 mEq, the chloride 86 mEq, and the carbon dioxide 39 mEq per liter. Lumbar puncture yielded clear, col- orless cerebrospinal fluid under normal pressure; the fluid contained 1 red cell per cubic millimeter; the protein was 33 mg per 100 ml. On the following day the patient was stuporous and unable to carry out requests. Acetazolamide (Diamox) was adminis- tered. On the fourth hospital day the sodium was 146 mEq, the chloride 96 mEq, the potassium 2.2 mEq, and the carbon dioxide 35 mEq per liter. The dose of potassium chloride elixir was increased to 10 ml four times daily. On the sixth hospital day spironolactone (Aldactone-A) was begun. A diagnos- tic paracentesis yielded clear, yellow fluid contain- ing 550 red cells and 50 white cells per cubic milli- meter; the protein was 0.9 gm per 100 ml; cytologie examination was negative. An upper gastrointestinal series revealed small esophageal varices and hepa- tosplenomegaly. A scan of the liver and spleen, using 99Te, revealed multiple discrete defects in the liver compatible with neoplastic deposits. On the seventh hospital day the hematocrit was 35 per cent, and the white-cell count 5700. The potassium was 2.9 mEq, and the carbon dioxide 32 mEq per
liter. Acetazolamide was discontinued. An electroen- cephalogram showed a mildly abnormal pattern of diffuse slow activity. On the ninth hospital day the potassium was 3.0 mEq per liter. A barium-enema examination showed diverticulitis of the sigmoid colon.
A percutaneous liver biopsy was performed.
DIFFERENTIAL DIAGNOSIS
DR. DANIEL 1). FEDERMAN *: This sixty-seven-year- old man had a history of alcoholic excess but with no known complications. One year before admission he had a seizure and pneumonia, both of which are common in association with alcoholism, but neither appears relevant to the problem at hand. The ankle edema that occurred three months later provides the first significant diagnostic clue. There are three main mechanisms for the development of ankle edema to be considered - a decrease in cardiac output, a decrease in oncotic pressure of the plasma due to a low serum albumin content and venous obstruction. Any two or all three of these factors may coexist, and each can be secondarily exacerbated by a decrease in the effective circulating volume, which triggers the renin angiotensin mechanism and ultimately produces an increase in aldoste- rone.
Of the physical findings on admission, the vital signs are not particularly helpful except for the ab- sence of hypertension. The normal neck veins and the lack of significant cardiac abnormality tend to exclude heart disease as the basic mechanism for the edema dating back nine months. The presence of ascites suggests both hypoalbuminemia and ve- nous obstruction. The liver was enlarged and ques-
*Associate physician, Massachusetts General Hospital; assistant professor of medicine, Harvard Medical School.
tionably nodular, raising the question of either tu- mor nodules or regenerating nodules, both of which are sometimes palpable. The splenomegaly is a point in favor of portal venous obstruction and against metastatic tumor. Without more history the atrophy of the testes is difficult to interpret. If they had always been small the patient probably had Klinefelter’s syndrome, but without such a history I have to assume that the atrophy was acquired. Ac- quired testicular atrophy has two main mechanisms - inflammatory disease of the testis such as mumps and acquired gonadotropin deficiency, for which there are several causes, one being tumor destroy- ing normal pituitary tissue. The pituitary gland is probably the only endocrine organ in which meta- static disease is an important cause of hypofunction. Gonadotropin deficiency can also be produced by too much estrogen; the cirrhotic patient’s delayed metabolism of estrogen may lead to high estrogen levels and thus to gonadotropin deficiency.
How can the laboratory data help to differentiate the diagnostic possibilities? The presence of bile in the urine suggests either parenchymal or obstructive hepatic disease. Hemolysis apparently was not a big factor, and, of course, the patient was not anemic. The leukocytosis suggests a component of infection, but seven days later the white-cell count was nor- mal, and there is no other evidence of infection. The bilirubin, SGOT and alkaline phosphatase val- ues are consistent with either parenchymal or ob- structive liver disease, and I therefore cannot make a choice between the two at the moment. The nor- mal albumin value, however, excludes one of the three main mechanisms for edema. Sherlock and her colleagues have pointed out that the presence of ascites in association with a very low serum albu- min level implicates hypoproteinemia as a big factor, whereas the presence of ascites in association with a reasonably well maintained serum albumin level implies a major degree of portal obstruc- tion.
Thus far, the negative cardiac examination and the normal serum albumin value have excluded two of the three causes of edema that I listed. The hepa- tomegaly and deranged liver function are consist- ent with the concept of portal venous obstruction, and I must decide whether that diagnosis explains the whole picture and specifically the hypokalemic alkalosis.
In discussing the pathogenesis of hypoka- lemia one is supposed to mention a nutritional deficit, but it must be an extremely rare cause. Vast- ly more common is gastrointestinal loss, through diarrhea, vomiting or a fistula, none of which is mentioned in this case record, or renal loss. A major cause of renal loss of potassium is the use of diuret- ies, and for this reason it would be important to know how much diuretic this patient was taking. Hypokalemia also occurs with various types of or-
ganic aciduria, such as diabetic acidosis, and when renal acidification is defective, as with renal tubular acidosis of various kinds. In such cases, however, the carbon dioxide is low and the chloride may be high. Potassium-losing nephritis is another possibili- ty to be considered, but the history. and the findings in the urinary sediment do not provide much sup- port for that diagnosis. Finally, there is excess of adrenocortical hormones, the principal ones being cortisol and aldosterone. Cortisol, although mainly useful as a glucocorticoid, does lead to significant salt retention and potassium excretion. It also pro- duces glucocorticoid effects such as mooning of the face, thin skin, plethora, osteoporosis and fractures. None of these features were observed in this case, and in addition there was no hypertension. So for the moment I shall discard cortisol excess as the main problem and turn to a consideration of aldosterone.
Aldosterone excess is found in association with either primary or secondary hyperaldosteronism, and there are points in this case record favoring each variety. Primary aldosteronism is essentially a hypertensive disorder without edema. Hypokalemia is common and according to Kaplan’ almost a uniform finding, although Conn and his associates? have not found it so. These patients have a low potassium level, a normal or high sodium level, hypertension and no edema. In contrast, the patient under discussion did not have hypertension and did have edema, and thus the likelihood of primary al- dosteronism is very small. Furthermore, that diagno- sis would not account for the rest of the picture, including the hepatosplenomegaly, since these pa- tients have benign, usually rather small adrenal adenomas. Secondary aldosteronism, on the other hand, is a very attractive diagnosis in this case. It occurs with renal ischemia of various etiologies, but we have no evidence for such a mechanism. It also occurs whenever there is a decrease in the so-called effective circulating volume, which has been postu- lated in cirrhotic patients with hypoalbuminemia or portal venous obstruction, or both, and in patients with heart disease and congestive failure. These patients do not have the escape from sodium reten- tion that occurs with primary aldosteronism, and thus progressive edema develops.
In cases of secondary aldosteronism one does not necessarily find very high aldosterone excretion values. To understand this, one must recall that aldosterone is almost completely cleared from the plasma by a single passage through the liver. One can thus refer to a metabolic clearance rate very similar to the clearance of creatinine or urea by the kidney. The aldosterone secretory rate (ASR) in micrograms per twenty-four hours is the product of the plasma level in micrograms per liter times the metabolic clearance rate (MCR) in liters per twenty- four hours:
ASR µg/24° = [Aldosterone]PLASMA µg/L × MCR L/24°.
From this equation it is clear that when the MCR falls the plasma aldosterone level can rise with no change in aldosterone secretion. Thus, in patients with defective hepatic metabolism the tissues can be exposed to elevated levels of aldosterone with- out measurably high levels of secreted or excreted aldosterone.
The diagnosis of secondary aldosteronism, there- fore, seems to fit quite well in this case. It is com- patible with the history, physical findings and labo- ratory data indicative of primary hepatic disease, venous obstruction, ascites and peripheral edema. However, there are two very disturbing points. One is that in cases of secondary hyperaldosteronism the potassium level is seldom as low as in this case. One reason postulated to explain the absence of severe hypokalemia is that not very much sodium reaches the distal tubules of the kidneys, where sodium and potassium are exchanged. The basic defect is a de- crease in effective volume and in filtration. As less sodium gets to the distal tubule there is less exchange, and thus the serum potassium level is not usually very low. The second crucial point is that the sodium level in cases of secondary hyperaldosteronism is usually low. Along with the basic defect of diminu- tion in the circulating volume and renal perfusion there is water retention, which results in a low serum sodium level combined with an expanded total body sodium content. In this patient the serum sodium level was normal when he came in and had risen four days later.
Recognizing that these findings need an explana- tion, we might turn to the electrocardiogram and the x-ray films at this point.
DR. WILLIAM F. MCNEELY: The tracing (Fig. 1) shows a normal rhythm at a rate of approximately 70. The T waves are generally low in the standard leads and inverted in Leads 1, 2 and aVL as well as all the precordial leads. The QT interval is pro- longed. The R wave is prominent in Leads V4 and V5. I am suspicious of left ventricular hypertrophy from the voltage alone, but it is not diagnostic, and I think that the T-wave changes represent an elec- trolyte abnormality for the clinician to investigate.
DR. FEDERMAN: Are they consistent with hypoka- lemia?
DR. MCNEELY: With hypokalemia or hypocalce- mia, or both.
DR. FEDERMAN: The calcium level was slightly low but probably not out of keeping with the albu- min level. I suspect that the electrocardiogra pattern reflected the hypokalemia, which was much more dramatic.
DR. JOSEPH T. FERRUCCI, JR .: The films of the chest taken on admission (Fig. 2) demonstrate a few ill defined densities at the lung bases compatible with areas of pneumonitis or atelectasis. The heart is at the upper limit of normal in size. A few old rib
fractures are visible on the left side. The remainder of the lung fields and the pleural spaces are clear. On the films of the skull the sella turcica appears normal.
The films of the abdomen and the upper gastroin- testinal series show enlargement of the liver and evidence of ascites, as indicated by separation of slightly dilated small-bowel loops and a hazy, gray appearance of the abdomen. The splenic contour is indistinct because of the ascites, but there is soft- tissue fullness in the left upper quadrant that proba- bly represents an enlarged spleen. Small esophageal varices are suggested. The stomach and duodenum appear normal. The 99Te liver scan discloses multi- ple discrete defects compatible with neoplastic deposits. The films from the barium-enema exami- nation demonstrate numerous diverticula in the sigmoid colon, with a few specks of barium that appear extraluminal and suggest microperforations. I think that a radiographic diagnosis of diverticulitis is warranted. I see no evidence of a neoplasm in this region.
DR. FEDERMAN: One of the dominant features of the clinical course in the hospital was progressive deterioration, with the development of asterixis, obtundation, decreased mental clarity and later stu- por, all despite partial correction of the hypokalemia and almost complete correction of the acidosis. The lumbar puncture disclosed no evidence of localized or metastatic disease and was thus consistent with a metabolic abnormality as the basic cause of the central-nervous-system troubles.
In addition, he had a “resistant“ hypokalemia. I put resistant in quotation marks because the severe degree of potassium deficiency suggested by the serum potassium level was probably not fully met by the doses of potassium that were administered. I come back to the question of the extent to which the chronic potassium deficit can be ascribed to the routine use of diuretics. Ordinarily, determination of the urinary potassium content is a fast way to make this distinction. In a patient with secondary aldo- steronism who is being treated with a diuretic the urinary potassium level may be strikingly elevated, but when the diuretic therapy is stopped the uri- nary potassium loss should decrease rapidly. If the patient is hypokalemic with a low urinary potassium level when off diuretics it suggests in retrospect that the diuretics were a big factor in producing the hypokalemia. On the other hand, if the urinary po- tassium level remains high there is a suggestion that something else is adding to the trouble. These data are not available in this case. We can say, however, that the hypokalemia persisted despite treatment with an aldosterone antagonist. Although spironolactone usually requires two to four days for appreciable effect and although the potassium was 3.0 mEq per liter when last measured, it seems fair to say that there was not a dramatic response to this
drug. If that is true, we have further evidence that the problem was not aldosterone excess.
I think that there is another way to account for the whole illness, and that is on the basis of a spe- cial type of cortisol excess that has been associated with ACTH-producing tumors. This syndrome was first described in 1928 by Brown.3 In the 1950’s 2 examples of it were discussed at clinicopathological conferences at this hospital.43 In 1962 Liddle’s group” showed that there were increased ACTH levels in the tumor and in the plasma and de- creased levels in the pituitary gland and thus estab- lished the fact that the tumor was making a sub- stance similar to ACTH. Sixty per cent of these tumors have been in the lung, usually oat-cell carci- nomas, about 10 per cent have been in the thymus, and 10 per cent have been in the pancreas, usually islet-cell tumors of the body or tail. Dr. Cohen and Dr. Castleman? and others” have reported a few car- cinoids that produced a similar picture. These tu- mors have usually presented as bronchial adenomas; some have been seen on x-ray films, but others only at autopsy.
It is well known that these patients may have dra- matic elevation of the plasma and urinary steroid levels, without a cushingoid appearance. The latter is absent because a change in the facies requires time to develop, whereas this disease has usually progressed rapidly to death. Therefore, hypokalemia and weakness have dominated the clinical reports. Edema, however, has not been common, and I should like to propose two mechanisms that might have contributed to its prominence in this man. Cortisol is predominantly metabolized by reduction of the 4-5 double bond in its A ring.
CH2OH
1
c=0
HO
OH
C
D
A
B
HO
The resulting dihydrocortisol is physiologically inactive. This step is slowed in patients with severe parenchymal liver disease, and I suggest that in this man, secondary to alcoholic cirrhosis or metastatic liver disease, or both, there was a combination of increased production and de- creased inactivation of cortisol, producing very high levels. It may then be asked why he did not have the escape from this stimulus to sodium retention that is seen in cases of primary aldo- steronism. I can only assume that there was enough intrinsic liver disease to prevent this phe- nomenon. Perhaps the splenomegaly is a signifi- cant item in this regard.
In conclusion, I shall say that this man had an
ACTH-producing tumor and shall leave the primary site unspecified for lack of positive evidence. I sus- pect that he also had parenchymal liver disease, perhaps complicated by metastases, and that it was physiologically significant.
DR. BENJAMIN CASTLEMAN: Dr. Kliman, what are your thoughts about this case?
DR. BERNARD KLIMAN: I also favor the diagnosis of an extraendocrine ACTH-secreting tumor and would add to the differential diagnosis the possibili- ty of an adrenocortical carcinoma. Such tumors may produce a clinical picture of this sort, without Cush- ing’s syndrome. The most anaplastic types seem to be associated with enzyme deficiencies that result in relatively limited cortisol synthesis until the tumor has metastasized and become very large. Some have been associated with edema as well. I have admin- istered spironolactone to a patient with Cushing’s syndrome complicated by hypertension, but without any benefit.
DR. CASTLEMAN: Dr. Baker, what diagnosis would you make?
DR. WILLIAM H. BAKER: I fully agree with the diagnosis of an ectopic ACTH-producing tumor. The facts given fulfill the dictum that a patient over forty-five years of age who has severe hypokalemic alkalosis without any known cause such as diuretic therapy, which is the most common etiology, probably is harboring an ACTH-producing tumor. It’s of interest that Dr. E. Dillwyn Williams, of the Hammersmith Hospital, in London, who spent a year in your department, regards most of these tumors as oat-cell carcinomas morphologically, wherever they originate. However, there are a few reports of tumors originating in the gallbladder, ovary and elsewhere that produced ACTH but were not oat-cell in type. On the basis of Dr. Williams’s morphologie analysis one might postulate the com- mon pathological denominator that all these tumors are produced by a single cell entity. I must admit that I find that hypothesis attractive. Certainly, carci- nomas of the pancreas, thymus and lung and the bronchial adenoma are all similar morphologically. If this patient also had cirrhosis with splenomegaly the diagnosis of such an oat-cell tumor of the lung is even more likely. The hepatomegaly is explicable on this basis. Splenomegaly is unusual with meta- static tumors. Although it has frequently been stated that the cirrhotic liver is not a site of metastatic tumor, I have seen such cases many times. Without clinically demonstrable gallstones one can’t impli- cate a primary site in the gallbladder. I think that the most likely primary site in this case is the lung or possibly the pancreas.
DR. MCNEELY: Dr. Ferrucci, some radiologists state that the finding of multiple rib fractures with exuberant callus formation is a common occurrence in cases of hyperadrenocorticism. Forgetting for the moment that this patient drank too much and may
have had fractures on that basis, does the appear- ance of the fractures or callus suggest this diagnosis to you? Do you think it’s a valid sign?
DR. FERRUCCI: I do, but in this case I see no convincing evidence of generalized osteoporosis, which is the predisposing cause of multiple frac- tures in such patients. The films show no compres- sion fractures of the vertebras or excessive callus along the ribs. These look like ordinary rib frac- tures.
DR. FEDERMAN: We are now following a patient with Cushing’s syndrome, the presenting manifesta- tion of which was rib fractures. As far as the cell type in the ectopic ACTH syndrome is concerned, Williams9 believes that the occasional thyroid can- cers that have produced ACTH were medullary car- cinomas.
I think Dr. Kliman’s point is a nifty one, though, and I wish I had thought of it myself. The differential diagnosis devolves, then, upon the rela- tive rarity of the two entities, an adrenocortical carcinoma with hyperaldosteronism versus an ACTH-producing tumor. Which do you consider more likely, Dr. Kliman?
DR. KLIMAN: Statistically, an extraendocrine ACTH-producing tumor is more common.
DR. RICHARD G. SMITH: According to the history we obtained from the patient he had been receiving injections, probably mercurial injections, for two weeks every other day, and in addition had contin- ued the chlorthalidone therapy. Therefore, we be- lieved that the hypokalemia was primarily a diuretic effect. Can a cortisol-secreting tumor or ACTH- secreting tumor also lead to an increased serum sodium level?
DR. FEDERMAN: Cortisol can do everything that aldosterone does. There can be a normal or elevated serum sodium level with hypokalemia in associa- tion with cortisol excess, just as there can be in cases of aldosteronism.
DR. ELLIOT ALPERT: I wonder why you didn’t consider a primary tumor in the liver, perhaps se- creting ACTH.
DR. FEDERMAN: Perhaps I should have. Since there is no positive evidence of a primary site I decided not to guess.
DR. CASTLEMAN: What diagnoses did the students make in this case?
DR. ALBERT R. MARTIN: The majority of the stu- dents believed that the patient had Laennec’s cir- rhosis with a superimposed hepatoma, with a minor- ity favoring a diagnosis of metastatic carcinoma and cirrhosis. Mr. Re and Mr. Schlenker discussed the case together, and the latter will present the findings.
MR. JAMES D). SCHLENKER: Our diagnosis is a hepatoma, with Laennec’s cirrhosis and diverticulitis. We could not rule out the possibility of ACTH se- cretion by the neoplasm.
DR. FEDERMAN: Do you think that ACTH and glucocorticoid excess was the cause of the physio- logic trouble, or do you attribute it to secondary hyperaldosteronism?
MR. RICHARD N. RE: We didn’t want to make a final statement in that regard without knowing the urinary potassium level. There is a definite sugges- tion in the case record that there was ACTH pro- duction by the tumor, and we could not eliminate that possibility but thought that the absence of hy- pertension was significant. With regard to the possi- bility of ACTH production by hepatomas, we did find one case report, in the Rocky Mountain Medi- cal Journal,10 of an intraductal carcinoma that secreted ACTH.
CLINICAL DIAGNOSES
Metastatic tumor in liver, ? primary site.
Laennec’s cirrhosis.
Diuretic-induced hypokalemia.
DR. DANIEL D. FEDERMAN’S DIAGNOSES
Ectopic ACTH production by malignant neo- plasm.
Cirrhosis of liver.
? Metastases in liver.
PATHOLOGICAL DISCUSSION
DR. RICHARD B. COHEN: The biopsy of the liver revealed metastatic carcinoma, which could not be classified because of the relatively small fragment of tissue available for study. After the biopsy the pa- tient lived for two weeks, during which he received orally administered potassium daily and was also given spironolactone.
At autopsy a primary oat-cell carcinoma was found in the right lower lobe of the lung. The tumor, which was only 2 cm in diameter, was the source of extensive metastases in the liver. There was no cir- rhosis. A small focus of tumor cells was seen in the pancreas. The most interesting findings were in the adrenal glands. The right adrenal gland was slightly enlarged, without nodules. Microscopically, the cor- tex was normal, with the expected distribution of fat in the fascicular zone (Fig. 3). It was clearly the unremarkable adrenal gland seen routinely at autopsy. In contrast, the left adrenal gland was massively enlarged, weighing 15 gm, without gross evidence of cortical nodules or metastases. The cortex was devoid of lipid and three times the normal width, with the enlargement in the fascicular-reticular por- tion (Fig. 4). The cell component was largely of the compact variety (Fig. 5). This appearance is charac- teristic of a cortex responding to intense ACTH stimulation and has always been a bilateral phe- nomenon in patients with ACTH-producing tumors. In this case it was unilateral. No metastatic tumor was observed in the right adrenal gland, which appeared entirely normal histologically. In the left
FIGURE 3. Normal Right Adrenal Gland. (X38) Note the lipid vacuoles in the fascicular zone.
FIGURE 5. Higher Magnification of the Left Adrenal Cortex Com- posed of Compact, Lipid-Poor Cells. (X90)
FIGURE 4. Left Adrenal Gland, with Marked Widening of the Cor- tex Composed of Fascicular and Reticular Cells. (X38)
adrenal gland, however, there were microscopic clusters of tumor cells, largely confined to the sinu- soids (Fig. 6), and the histologic appearance was so typical of a response to ACTH that it is logical to
conclude that this adrenal gland was receiving an intense perfusion of ACTH from small metastases in local blood vessels. It is probable that the other
adrenal gland, in the absence of such metastases, was not receiving sufficient ACTH to produce a significant effect. I had never seen a case in which there was marked, diffuse, non-nodular, unilateral stimulation of the adrenal cortex in this manner.
The oat-cell carcinoma of the lung is the tumor most likely to be the source of extraendocrine ACTH production. It is generally regarded as a highly undifferentiated tumor. It is indeed highly undifferentiated, but on careful study of many sec- tions through the primary tumor and its metastases one frequently can find the pattern of ribboned cells and small acini that the pathologist associates with the histology of carcinoid tumors, particularly those arising from the foregut. This histologic pat- tern is typefied in the bronchial adenoma of the carcinoid type. In the reported study to which Dr. Federman referred we pointed out the basic similar- ity of the histologic pattern in 2 bronchial adenomas associated with Cushing’s disease, an oat-cell carci- noma associated with Cushing’s disease and the epithelial type of thymoma associated with Cush- ing’s disease.7 In the case under discussion we found a similar carcinoid-like pattern of prominent areas of ribboning and acinar formation in both the primary oat-cell tumor and the hepatic metastases (Fig. 7 and 8).
It is interesting that with few exceptions the tu- mors of nonendocrine origin associated with ACTH production are of foregut origin. These include oat-
cell carcinoma, bronchial adenoma (carcinoid), thy- moma and medullary carcinoma of the thyroid gland. Carcinoids of the stomach and pancreas as well as islet-cell tumors of the pancreas also belong in this group. Unrelated tumors have been implicated in ectopic ACTH secretion, but they are unusual and often difficult to document.11
We have, then, to a considerable extent an inter- relation of these tumors in terms of origin and histo- logic appearance. This similarity raises another point of interest. If the unusual polypeptide secre- tion results from the absence of a repressor normal- ly present in extrapituitary tissue, it is not a random loss but apparently to a large extent confined to tumors of a particular origin with histologic similari- ties. This becomes even more intriguing when one recalls that the anterior pituitary gland is of foregut origin.
DR. BAKER: I might add two more biochemical points. This type of cell is also capable of pro- ducing tryptophane metabolites, with and without association with the classic carcinoid syndrome. Secondly, Liddle and his associates12 have found melanocyte-stimulating hormone (MSH) in addition to ACTH in all such tumors examined as of 1966. Granted, there is an amino acid sequence similar to ACTH and MSH, but MSH has been identified specifically by immunoassay. We have just recently seen our first case of oat-cell carcinoma of the lung with Cushing’s syndrome and hyperpigmentation. As yet we do not have values for MSH in the blood or urine.
DR. FEDERMAN: Another point that this case illus-
trates is the evolutionary significance of the separa- tion of tropic hormones from their target glands. A target gland was flooded with a tropic hormone, in this instance from an ectopic source within the tar- get organ. The poisonous consequences are a beau- tiful illustration of why tropic hormones should be produced at sites distant from their target glands.
DR. KLIMAN: Doesn’t this separation facilitate the feedback mechanism for regulation of the tropic hormone?
DR. FEDERMAN: Yes, one couldn’t have feedback locally. Every endocrine gland has to be protected against poisoning by its own substance. Otherwise, the adrenal gland would always have Cushing’s syndrome, the testis testosterone poisoning, and the thyroid gland thyrotoxicosis. One probably couldn’t combine the subtleties of feedback control with pro- tection against hormonal autointoxication.
ANATOMICAL DIAGNOSES
Oat-cell carcinoma, right lower lobe of lung, with metastases to liver, pancreas and left adrenal gland.
Unilateral hyperplasia, marked, left adrenal cor- tex, involving fascicular and reticular zones.
REFERENCES
1. Kaplan, N. M. Hypokalemia in hypertensive patient: with obser- vations on incidence of primary aldosteronism. Ann. Int. Med. 66: 1079-1090, 1967.
2. Conn, J. W., Cohen, E. L., Rovner, D. R., and Nesbit, R. M. Normokalemic primary aldosteronism: detectable cause of curable “essential” hypertension. J.A.M.A. 193:200-206, 1965.
3. Brown, W. H. Case of pluriglandular syndrome: “diabetes of bearded women.” Lancet 2:1022, 1928.
4. Case Records of the Massachusetts General Hospital (Case 39011). New Eng. J. Med. 248:29-35, 1953.
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