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Pheochromocytoma masquerading as overwhelming infection
Clinical communications
Pheochromocytoma masquerading as overwhelming
infection
Herbert L. Fred, M.D.* Dmid P. Allred, M.D. Harold E. Gurber, M.D. Kluus Retiene, M.D. Hurry Lipscomb, M.D. Houston, Tex.
P
heochromocytoma properly has been termed the great mimic.l This tumor has masqueraded chiefly as essential2 or malignant3 hypertension, diabetes mellitus,4 thyrbtoxicosis,5 or various types of neurosisfi Occasionally, its manifestations have l)een mistaken for those of gastrointestinal lAeeding,T myocardial infarction,7-g ai>dominal catastrophies,gslo gallstone colic,11 cerebral tunlor,11 primary renal disease,11,12 ::cute adrenal insufficiency,1z toxemia of pregnancy,13 acute pancreatitis,14 carcinoid syndrome,14,15 acute porphyria,15 pulmonary em1301us,15 abdominal15 or idiopathic16 epilepslr, tetany,17 or cranial arteritis.la The case to be reported is that of a woman whose terminal illness we attributed clinically to overwhelming bacterial infection. Proof of infection, however, never was obtained. ATore importantly, necropsy disclosed an unsuspected pheochromocytoma. In this communication we shall present evidence to support our belief that the tumor was responsible for the clinical features observed. From
Case report A 62-year-old Caucasian woman was brought to the hospxtal on March 7, 1965, because of stupor. During the preceding 10 years, she had been treated intermittently for diabetes mellitus and hypertension, but details of these illnesses were not available. The patient apparently had been asymptomatic until 4 days before admission, when she began to hax.e abdominal discomfort and >-omiting, especially after eating. At about the same time, she experienced feverishness and a nonproductive cough. Approximately 6 hours before admission she became \veak and hyperactive. Her physician administered 20 mg, of prochlorperazine (Compazine) orally and 25 mg. of chlorpromazine (Thorazine) rectally, but her clinical status rapidly deteriorated and she was referred to the hospital. Physical examination revealed a semicomatose, restless, slightly obese woman xvho wxs sweating profusely about the face and trunk. She breathed deeply at a rate of 32 per minute and had a rectal temperature of 103.4T., a pulse of 140 regular beats per minute, and a blood pressure of 70/O mm. Hg. Her face was flushed, hut her arms anti legs were cold and cyanotic. There ivere r5les posteriorI>. ok er the lower portion of the right lung. The ahdomw was distended hut soft, and the bowel sounds were absent. The initial hematocrit value was 53 per cent; 4 days later, it was 46 per cent, at which level it
the Departments of Medicine, Pathology, and Physiology, Bayiur tJniversity College of Medicine, and Ben Taub General Hospital, Houston, Tex. This study was supported in part by Grant No. AM-04122 from the LTnited States Public Ilealtb Service, National Institutes of Heatth, Grant No. 9-2323 from the Nationat Aeronautics and Space z\dministration, and Grant So. lit
1.50
Fred, Allred, Garber, Retiene, and Lipscomb
remained throughout the hospital course. Multiple total leukocyte counts ranged between 14,500 and 23,600 per cubic millimeter, with differential counts averaging SO per cent polymorphonuclear leukocytes, 5 per cent juvenile forms, and 15 per cent lymphocytes. On a smear of the peripheral blood, the erythrocytes were normocytic and normochromic and the platelets appeared to be present in adequate numbers. LTrinalyses showed a pH of 6.0, a specific gravity ranging between 1.011 and 1.024, a 1+ reaction for protein, and a negative to 3+ reaction for sugar; the spun urinary sediments contained 5 to 8 erythrocytes and 0 to 3 leukocytes per high-power field. A stool specimen was guaiac negative. LAt the time of the patient’s admission, the concentration of blood urea nitrogen (BUN) was 86 mg./lOO ml.; blood glucose, 300 mg./lOO ml.; serum COz, 20 130 mEq./L.; chloride, 84 mEq./L.; sodium, mEq./L.; and potassium, 2.6 mEq./L. Two days later the BUN had fallen to 40 mg./lOO ml.; the serum electrolyte values were within normal limits; and studies of the arterial blood revealed a pH of 7.49, a Pcoz of 31 mm. Hg, a Paz of 59 mm. Hg, and an Oz saturation of 91 per cent. Three days after admission, the BUN was 27 mg./lOO ml. Roentgenograms of the chest, a radioisotopic scan of the lungs, and an excretory urogram were normal. Plain abdominal roentgenograms showed gaseous distention of the small and large bowel. Bronchoscopy on the second hospital day disclosed no abnormality. Serial electrocardiograms revealed
sinus tachycardia and nonspecific S-T and T-wave changes. Conventional studies of the cerebrospinal fluid gave normal results. No growth of organislns appeared in thirteen blood cultures, two urine cultures, one stool culture, one cerebrospinal fluid culture, and tracheal washings. The initial clinical impression \vas gram-negative bacteremia. Because of the tachypnea, hyperpnea, and fever, multiple pulmonary emboli and bacterial pneumonia were other diagnostic considerations, The elevated hcmatocrit value and history of recent vomiting suggested that the patient also was signilicantly dehydrated. Therapy instituted shortly after the patient’s admission consisted of physiologic saline, metaramino1 (Araminc), tetracycline, streptomycin, and penicillin. Within 4 hours, the blood pressure rose to 120/75 mm. Hg and use of the vasopressor was discontinued. During the first 2 hospital days, 12 1,. of physiologic saline and 3 L. of 5 per cent dextrose in water were administered intravenously, the total urine output being <3 I,. Twenty-four hours after admission, at a tilne when the patient had received 9 L. of fluid intravenously and had shown clinical improvement, her rectal temperature rose abruptly to 106.6’F. COW comitantly, her pulse rate increased to 160 regular beats per minute, her blood pressure rose to 160/100 mm. Hg, and her respiratory rate increased to 32 per minute. iI:et sponges were applied to the skin, and aspirin suppositories were administered. Promptlv
I60 I40 I20 ,~
PULSE Iboah/min.l
00
TEMPERATURE ( RECTAL-W
‘02
blwn.iig 1
WOOD PRESSURE
40 RESPIRATIONS t 1 min.)
32 24 I6
ANTIBIOTICS
Fig.
1. Pertinent
clinical
and
therapeutic
data.
HOSPITAL . -
DAY -
infection
151
the extract. Although the concentration rine in this pheochromocytoma was not high,* the tumor’s secretory potential is by the fact that the net amount of tissue epinephrine was ten to twenty times the
of epinephabnormally attested to containing normal.
Pheochromocytoma rn~q~u~rding
thereafter, her temperature fell to 98.6’F. A short time later, her blood pressure dropped to 120/70 mm. Hg, but her temperature rose again and remained elevated throughout the hospital course (Fig. 1 ). During the third hospital day, the patient’s abdomen rapidI>. became more distended. Examinzition revealed a large, tender, cystic mass in the right lower quadrant. Because plain abdominal roentgenograms and barium enema examination suggested cecal volvulus, celiotomy was performed early on the fourth hospital day. This procedure disclosed neither volvulus nor other mechanical obstruction. :In extremely dilated cecum was decompressed and fwe tears in its serosa were imbrirated. The surgeon stated that both kidneys and adrenal glands urere m)rmal to palpation. Although the patient withstood the entire procedure tvell, review of the operatic-e record showed that, during an apparently uneventful i~~duction of anesthesia with thiopental sodium, a transient rise in btood pressure from normotensive levels to 190/130 mm. Hg had been recorded. Postoperatively, the patient con&lued to exhibit fever, tachypnea, tachycardia, ilcus, and leukovytosis. Three dais after celiotomy, a Grade l/6 precordial systolic ejection murmur became audible for the first time. It was heard best at the left sternal border in the fourth intercostal space. LVithin 24 hours the murmur increased in intensity to Grade 3/6 and bacterial endocarditis was suspected. Therefore, large doses of penicillin and methicillin (Staphcillin) were administered, but the patient clied on the ninth hospital day. At nccr@sy, performed 6 hours after death, the only significant finding was an enlarged right adrenal gland weighing .50 grams. Its cut surface showed a gray-white meduliary tumor surrounded by cortical remnants. Part of the gland was covered with Zenker’s solution, aud the tumor in the medutla turned a mahogany color, indicating the presence of ca~echolamines.‘g Histologically, the cortex was normal and distinct from the adjacent neoplastic tissue. The tumor cells were pleomorphic and ranged ill size from 10 to 60~. Their cytoplasm was abundant and had uniformly fine granules which gaxre a positiw reaction to Gonwri’s chromaffin stain. Foci of hemorrhage and necrosis were present in the vascutar stroma. .An oil red 0 stain for neutral fat was positive in the cortex but not in the adjacent tumor. These histologic and histochemical lindings were considerecl to be typical of pheochromocytoma. The tumor \vas assayed biologically and chemically. Akid-saline tissue extracts were brought to concentrations of 0.1 mg., 0.5 mg., and 1.0 mg. of tissue per 0.2 ml. of solvent. The increase in arterial blood pressure of pithed rats was used as a measure 0r prebsor wtivitl,. ~lnkno~ns lvere assayed agaiust standards of 0.0001 mg., 0.0005 mg., and 0,001 mg. oi l-epincphrine. .4n cpincphrine content of 0.6 nag. per gram of tumor tissue was calculated in 3 six-point biologic assays. Chemical analysis of the tissue extract using ethylenediamine revealed a fluorescing reaction product identical in behavior to that of authentic l-epinephrine. The calculated concentration of this product, presumably epinephrine, was 0.6 mg. per gram of tumor tissue. No norepinephrine \vas found in
(1.~ovuwhelming
Discussion There is strong support for our belief that the tumor in this patient was responsible for the clinical features observed. First, the histoq; of hypertension2J and diabetes mellitus4 IS consistent with a functioning pheochromocytoma. Second, abdominal pain, nausea, and vomiting are frequent manifestations of this tumor.21 Third, a pronounced sensitivity to the hJ,potensive effects of phenothiazines has been observed in patients with this neoplasm.14,22 Fourth, patients larith pheochromocytoma are knobvn to exhibit various combinations of fever,2J spontaneous hypotension,15s24b25 tachycardia,26,27 tachypnea,g,28 flushed facies 11z14s\\reating,2s-s1 paralytic ileus,g,sZ and leu’kocytosis.8 Fifth, hypertension developed transiently during induction of anesthesia.33 Sixth, extensive antemortem investigation produced no proof of infection. Seventh, the pheochromoc>toma was the only significant finding at a carefully performed ne(‘ropsy. Finally, there is at least one other case of pheochromocytoma, strikingly similar to ours, in which the presenting manifestations initially. kvere attributed to ovcrwhelming infection. HamrinZ5 described an acutely ill, .54-year-old lvoman lvith epigastric cramps, vomiting, fever, tach>-cardia, leukoqtosis, azotemia, an elevated hemoglobin value, and a blood pressure of 130190 mm. Hg. Less than 2 days later, her temperature rose to 104.9’F., and she developed profound shock. The presumptive diagnosis was sepsis. After treatment with norepinephrine, hydrocortisone, and antibiotics, her clinical status promptI! improved. fluring the next 24 hours, 3,000 ml. of glucose and 4,000 ml. of saline solution \vcrc administered intravenously. Sut)sequently, a slightly tender mass, thought at first to represent a perinephric abscess,
152
Table
Fred,
Allred,
Gurber,
Retiene,
and Lipscomb
I. The effects of catecholanaines
on various
orgcln
systems ,in man
~ I
Epinephritle
Eject
1~ i Proposed ~ rereptw
i
Norepieephrine
Proposed receptor
.Tign
1 .Tign I
HearPJ’ Rate Strength of contraction output Blood pressureso,3’ .Systolic Diastolic Mean arterial pressure I’eripheral resistance (total) Respiration38 Rate Depth Miscellaneous Intestinal tonus3g Glycogenolysis?~ Calorigenic actions7 Leukocytes4o Sweat gland activity*’
kroreceptors 13
@
a and
[j
Hypotension
t
Tachypnea Hyperpnea
t t
Paralytic ileus IHyperglycemia Fever Leukocytosis Hyperhidrosis
1
Reflex
bradycardia
Systemic sion I’eripheral visceral
CY
hypertenand ischemia
Tachypnea Hyperpnea a and
p
Paralytic
ileus
*In the heart
was palpated in the upper region of her right kidney. Further studies showed that the mass was a pheochromocytoma which secreted epinephrine predominantly. The tumor was removed and the patient’s symptoms subsided. The features suggesting infection in Hamrin’s patient and in our patient can be attributed partly or entirely to epinephrine. In this regard, the receptor theory proposed by Ahlquist34 and modified by FurchgotV5 is helpful in understanding the systemic effects of epinephrine and norepinephrine. According to this theory, cells have specific receptors, possibly enzymes, that interact with a catecholamine to produce a given response (Table I). This classification proposes alpha (a) receptors for contraction of smooth muscle, beta (B) receptors for relaxation of smooth muscle and for increased rate and strength of cardiac contraction, and a combination of alpha and beta receptors for inhibition of contraction of intestinal smooth muscle.3g In general, norepinephrine stimulates alpha receptors, and epi-
nephrine stimulates beta receptors; however, each hormone activates both receptor sites to varying degrees. Some of the findings in the present case deserve special comment. The hypotension undoubtedly resulted from hypovolemia brought about by recurrent vomiting and sequestered fluid in the bowel lumen. There also may have been an extravasation of plasma into the interstitial space as a consequence of epinephrine-induced dilatation of precapillary vessels and constriction of postcapillary vessels. The patient’s subsequent toleration of massive replacement of fluid supports the contention that her intravascular compartment initially was contracted. Possibly, the phenothiazines aggravated the hypotension. Since these drugs block alpha receptor (vasoconstrictor) activity,4z the administration of them to a patient with a predominantly epinephrine-secreting pheochromocytoma would leave beta receptor (vasodilator) stimulation unopposed and shock could supervene. Mild elevations in body temperature are common in patients with pheochromo-
Pheochromocytonu~
cytoma,23 and temperatures as high as 107’F. have been cited in some cases.28,43 Epinephrine acts in two ways to elevate body temperature. It increases the production of heat by augmenting cellular metabolisnl,44 and it decreases the dissipation of heat by producing intense cutaneous vasoconstriction.45 Such vasoconstriction is ascribed to an effect of this hormone on alpha receptors. It is unlikely that a deficit in fluid volume per se was a major cause of fever in our patient, since she remained febrile after rehydration. The mechanism of the heart murmur reespecially since no mains speculative, cardiac abnormalities were disclosed at necropsy. Accounts have been recorded, however, of loud apical,gz46 pulmonic,15a22 or aortic46 systolic murmurs and/or soft, diastolicgr47 murmurs that appeared in patients with pheochromocytoma either during9,22 or shortly afteP symptomatic paroxysms. Necropsy in one of these cases9 and right heart catheterization and pulmonaq angiograms in anothe+ failed to reveal a cause for the murmur(s). Jlost pheochromocytomas secrete either norepinephrine or a combination of norepinephrine and epinephrine.J* In the latter circumstance, norepinephrine usually predominates.4g By contrast, pheochromocytomas secreting only epinephrine are rare.6o Since the content of cathecholamines in the adrenal gland may diminish rapidly after death,:l lve cannot exclude the possihility that the tumor in our patient also contained norepinephrine. Nevertheless, the results of the analysis are consistent with most of the clinical features observed. Summary
A patient is described who had fever, hypotension, tachypnea, hyperpnea, tachycardia, sweating, flushed facies, and leukocytosis. Her hypotension responded to the replacement of fluid, but the other clinical abnormalities persisted, and were accompanied later by paralytic ileus, higher fever, and the development of a precordial systolic ejection murmur of progressively greater intensity. The clinical impression initially was gram-negative l)acteremia, and, finally, bacterial endocarditis. Antemortem proof of infection, however, never was obtained. At necropsy,
musqueruding
us overwhelming
irl,fxtiotl
1.53
the only significant finding was an UIISLEpetted pheochromocytoma containing epinephrine. Evidence is presented to support the contention that the tumor was responsible for the clinical features 016erved.
1. 2.
3.
4.
De Courcy, J. L.: Pheochr(~tlloc~t~~tll~l, ~~III. J. Surg. 86:37, 19.53. Goldenberg, M., Serlin, I., Edwards, ‘I.., and Rapport, >T, Al.: Chemical screening method> for the diagno& of pheochromoc> kwa. I. Norepinephrine and epinephrine in h~tmat~ urine, .kn. J. Med. 16:310, 1954. Pahner, R. S., and Cas~leman, B.: I’araganglioma (chromaffinoma, ~~heochr(~Ill~~,t~)rll~j of the adrenA gland simul&~g malignant hywtension. Report of a case, Xe\v England J. &led. 219:793, 1938. Freedman, P., iUoulton, R., Rosenheim, M. l,., Soencer. Ak G.. and 11’iilowhb\,, 11. :I.: I’hwochromocytoma, diabetes, and glb-cosuria, (@Iart. J, Med. 27:307, 19S8. Futterweit, I\:., Allen, L,, alid kloher, AI.: I’heochromocytoma xvith radioactive iodine uptake and electrocardiographic abnormalities: Cze report with a review of thyroid-adrenal medullat->. interrelationships, ~Ietabolism 11 :S89, 1962. Crede, R. H., and Kerr, I\.. J,: l’heochromocytoma: Report of a case with qmptoms simulating acute a&et!atkwks. l’ostgrad. Med. 11:288, 19.52. Vkick, J. H.: F’h~~e~hro~~l(~!~to~ll~~ presenting as oostural hvootension. Proc. Ro! . SW. 1lcd. 57k73, 1964: ’ French, C., and Campagna, F. A\.: I’heochromoc\?oma with shock, marked letkocytosis, and unusual electrocardiograms Case repcort and review of the 1iterattn-e. ;\nn. lnt. 1Ied. 55:1.!7, 1961. JellilTe, R. S.: I’h~le~~chr(~l~lo~~totll~~ presentijlg as a cardiac al>d abdomi~l:~l catastrophe, Brit. ILI. J. 2:76, 1952. Gilliland, I. C., and l)xniel, 0.: I’haeochromoq,toma presenting as all abdominal emergent>-, Bit. 31. J. 2:275, 19.51. Leather, H. bI., Shaw, I). B., Gates, J. I<., alid lfTalker, 1~. WI. : Six cabes of ~h~~eochr~~~ll(~~~t(~~~~~~ with unusual clinical manifestations, 13rit. 11. J. 1:1373, 1962. l~ough~on, C. R.: I’h~~eochro~~~~~c~.to~l~~~ -Report of a case with interesting aspects, >Ied. J. A~uskalia 2:4?1, 1960. Peelen, J. iv., and De Groat, ~1.: I’heochromocvtoma complicated by prernancv, Ani. f. 0l)bt. ~.
.5*
6.
7.
a.
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11.
12
13.
14.
15.
c>
.
.
1.54
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17. 18. 19. 20.
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23.
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25.
26.
27.
28.
29.
30.
31.
32.
33.
Fred, Allred, Gerber, Retiene, und Lipscomb
secreting phaeochromocy toma, lancet 2:904, 1961. Mortell, E. J., and IVhittle, J. I’.: Pheochromocytoma: Case report with certain observations on the pathologic physiolog>., J. Clin. Endocrinol. 5:396, 194.5. Sack, H., and Koll, J.: Cited by IIamrin.*~ McGill, R. J., and Davies, J. A H.: Phaeochromocytoma, Brit. M. J. 1:1698, 1962. Sherwin, R. I’.: Histopathology of pheochromocl-toma, Cancer 12:861, 1959. \.on Euler, lJ. S., Franksson, C., and Hellstrom, J. : Adrenaline and noradrenaline content of surgically removed human suprarenal glands, Acta Physiol. Scandinav. X:6, 19.54. Habermann, E. T., Millheiser, P. J., and Casten, D. F.: I’heochromocytomzi in the organ of Zuckerkandl presenting with gastrointestinal symptoms, J. Clin. Endocrinol. 24:334, 1964. Brady, I. A4.: Shock after administration of prochlorperazine in patient with pheochromocytoma. Report of a case with spontaneous tumor destruction, J..%.M.A. 169:1749, 1959. Smithwick, 1~. H., Greer, if:. E. R., Robertson, C. IV., and Wilkins, R. LfT.: Pheochromocytoma. :I discussion of symptoms, signs and procedures of diagnostic value, New England J. Med. 242:2S2, 1950. Ramsay, I. D., and Langlands, J. H. M.: Phaeochromocytoma with hypotension and polycythaemia, Iancet 2:126, 1962. Hamrin, B.: Sustained hypotension and shock due to an adrenaline-secreting phaeochromocvtoma, Lancet 2:123, 1962. Kahn, M. T., and Mullon, D. A.: Pheochromocytoma without hypertension. Report of a patient with acromegaly,, J..A.~l..X. 188:74, 1964. Davies, D. &I., Ross, J. H., Richardson, J. E., and Parry-Brown, A. I.: Experience lvith phaeochromocytoma, Postgrad. iX’Ied. J. 39:~?37, 1963. Belt, A. E., and Powell, T. 0.: Clinical manifestations of the chromaffin cell tumors arising from the suprarenal medulla. Suprarenal sympathetic syndrome, Surg. Gynec. & Obst. 59 :9, 1934. Kirkendall, if;. M., Liechty, R. I)., and C~ilp, I). A.: Diagnosis and treatment of patients with pheochromocytoma. Experiences at I~niversity Hospitals from 1941-1964, Arch. Int. ?VIed. 115:529, 1965. Delarue, N. C., and O’Brien, 11.: Pheochromocytoma: An important type of “curable” hypertension. A report of 11 cases and a review of the literature, Canad. J, Surg. 6:2.59, 1963. Gifford, R. W., Jr., Kvale, 1x7. F., Maher, F. T., Roth, G, M., and Priestley, J. T.: Clinical features, diagnosis and treatment of pheochromocytoma: A review of 76 cases, Proc. Mayo Clin. 39:281, 1964. Hughes, 1~. E., Bolt, D. E., and Hobson, Q. J. G.: Phaeochromocytoma: Presenting as resistant intestinal ileus, Proc. Roy. Sot. Med. 55:998, 1962. Crockett, K. A., Snow, E., and Rees, V. I~.: Pheochromocytomas as cause of unexpected
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operating room deaths, A4m. Surg. 27:395, 1961. Ahlquist, 1~. P.: A study of the adrenotrophir receptors, Am. J. Physiol. X3:586, 1948. Furchgott, R. F.: The receptors for epinephrine and norepinephrine (adrenergic receptors), Pharmacol. Rev. llA29, 1959. Ginsburg, J., and Cobbold, A. F.: Effects of adrenaline, noradrenaline and isopropylnoradrenaline in man, itz \Volstenholme, G. E. \\‘., and O’Connor, M. : Ciba Foundation Symposium. Adrenergic mechanisms, Boston, 1960, little, Brown and Co., pp. 173-189. Inner, I. R., and Nickerson, b1.: Drugs acting on postganglionic adrenergic nerve endings and structures innervated by them (sympatho mimetic drugs), in Goodman and Gilman,‘* pp. 477-520. \\Thelan, R. F., aiid Young, I. \;I. : The effect of adrenaline and nor:idrenaline infusions on respiration in man, Brit. J. Pharmacol. 8:98, 19.53. Furchgott, 1~. F.: Receptors for sympathomimetic amines, ;n \~‘olstenhohne and O’Connor,‘~‘~ pp. 246-252. Samuels, A. J.: Primary and secondary leukoqte changes following the intramuscular injection of epinephrine hydrochloride, J. Clin. Invest. 30:941, 19Sl. IIermann, H., and Mornex, I~.: Human tumour~ secreting cathecholamines. Clinical and physiopathological study of the pheochromocytomas, translated hy R. Crawford, New York, 1964, The Macmillan Co., pp. 167.169. Goodman, I-. S., and Gilman, A.: The pharmaological basis of therapeutics, ed. 3, New York, 1965, The M~mnill~~~~ Co., p. 171. Howard, J. E., and Barker, \V. H.: Paroxy.smal hypertension and other clinical manifestations associated with benign chromaflin cell tumors Bull, Johns Hopkins (ph~le(~chr(~tll(~c~-t~Jlll~l), Hosp. 61:371, 1937. Swanson, H. E.: Interrelations betweeii thyroxin ;md adrenaline in the regulation of oxygen coiisumption in the albino rat, Endocrinology~ 59:217, 19S6. Engel, F. I>., LIencher, \V. H., and Engel, G. I,.: “Epinephrine shock” as a manifestation of ‘a pheochrolll~)c~t~~ln~~ of the adrenal medulla. Report of a case with surcessful removal of the tumor, .\m. ]. h1. SC. 204:649, 1942. Emanuel, I). .I.. Rowe, G. G., Musser, M. .I., and Philpot, V. B., Jr.: Proloiiged hypotension with fatal termination after a phentolamine (Regitine) methanesulfontate test, J.A.M.A. 16lA36, 1956. Bernal, I’.: Cited by Mackeith, R.: Adrenasympathetic syndrome. Chromaffin tissue tumour with paroxysmal hypertension, Brit. Heart J. 6:1, 1944. Goodall, McC., and Stone, C.: Adrenaline and noradrenaline producing tumors of the adrenal medulla and sympathetic nerves, Ann. Snrg. 151~~91, 1960. Van Euler, IJ. S., and Strom, G.: Present status of diagnosis and treatment of pheochromocy,loma, Circulation 15:5, 19.57. Hermanu and hIornex,4’ p. 130. Ibid., p. 1.37.
Pheochromocytoma masquerading as overwhelming
infection
Herbert L. Fred, M.D.* Dmid P. Allred, M.D. Harold E. Gurber, M.D. Kluus Retiene, M.D. Hurry Lipscomb, M.D. Houston, Tex.
P
heochromocytoma properly has been termed the great mimic.l This tumor has masqueraded chiefly as essential2 or malignant3 hypertension, diabetes mellitus,4 thyrbtoxicosis,5 or various types of neurosisfi Occasionally, its manifestations have l)een mistaken for those of gastrointestinal lAeeding,T myocardial infarction,7-g ai>dominal catastrophies,gslo gallstone colic,11 cerebral tunlor,11 primary renal disease,11,12 ::cute adrenal insufficiency,1z toxemia of pregnancy,13 acute pancreatitis,14 carcinoid syndrome,14,15 acute porphyria,15 pulmonary em1301us,15 abdominal15 or idiopathic16 epilepslr, tetany,17 or cranial arteritis.la The case to be reported is that of a woman whose terminal illness we attributed clinically to overwhelming bacterial infection. Proof of infection, however, never was obtained. ATore importantly, necropsy disclosed an unsuspected pheochromocytoma. In this communication we shall present evidence to support our belief that the tumor was responsible for the clinical features observed. From
Case report A 62-year-old Caucasian woman was brought to the hospxtal on March 7, 1965, because of stupor. During the preceding 10 years, she had been treated intermittently for diabetes mellitus and hypertension, but details of these illnesses were not available. The patient apparently had been asymptomatic until 4 days before admission, when she began to hax.e abdominal discomfort and >-omiting, especially after eating. At about the same time, she experienced feverishness and a nonproductive cough. Approximately 6 hours before admission she became \veak and hyperactive. Her physician administered 20 mg, of prochlorperazine (Compazine) orally and 25 mg. of chlorpromazine (Thorazine) rectally, but her clinical status rapidly deteriorated and she was referred to the hospital. Physical examination revealed a semicomatose, restless, slightly obese woman xvho wxs sweating profusely about the face and trunk. She breathed deeply at a rate of 32 per minute and had a rectal temperature of 103.4T., a pulse of 140 regular beats per minute, and a blood pressure of 70/O mm. Hg. Her face was flushed, hut her arms anti legs were cold and cyanotic. There ivere r5les posteriorI>. ok er the lower portion of the right lung. The ahdomw was distended hut soft, and the bowel sounds were absent. The initial hematocrit value was 53 per cent; 4 days later, it was 46 per cent, at which level it
the Departments of Medicine, Pathology, and Physiology, Bayiur tJniversity College of Medicine, and Ben Taub General Hospital, Houston, Tex. This study was supported in part by Grant No. AM-04122 from the LTnited States Public Ilealtb Service, National Institutes of Heatth, Grant No. 9-2323 from the Nationat Aeronautics and Space z\dministration, and Grant So. lit
1.50
Fred, Allred, Garber, Retiene, and Lipscomb
remained throughout the hospital course. Multiple total leukocyte counts ranged between 14,500 and 23,600 per cubic millimeter, with differential counts averaging SO per cent polymorphonuclear leukocytes, 5 per cent juvenile forms, and 15 per cent lymphocytes. On a smear of the peripheral blood, the erythrocytes were normocytic and normochromic and the platelets appeared to be present in adequate numbers. LTrinalyses showed a pH of 6.0, a specific gravity ranging between 1.011 and 1.024, a 1+ reaction for protein, and a negative to 3+ reaction for sugar; the spun urinary sediments contained 5 to 8 erythrocytes and 0 to 3 leukocytes per high-power field. A stool specimen was guaiac negative. LAt the time of the patient’s admission, the concentration of blood urea nitrogen (BUN) was 86 mg./lOO ml.; blood glucose, 300 mg./lOO ml.; serum COz, 20 130 mEq./L.; chloride, 84 mEq./L.; sodium, mEq./L.; and potassium, 2.6 mEq./L. Two days later the BUN had fallen to 40 mg./lOO ml.; the serum electrolyte values were within normal limits; and studies of the arterial blood revealed a pH of 7.49, a Pcoz of 31 mm. Hg, a Paz of 59 mm. Hg, and an Oz saturation of 91 per cent. Three days after admission, the BUN was 27 mg./lOO ml. Roentgenograms of the chest, a radioisotopic scan of the lungs, and an excretory urogram were normal. Plain abdominal roentgenograms showed gaseous distention of the small and large bowel. Bronchoscopy on the second hospital day disclosed no abnormality. Serial electrocardiograms revealed
sinus tachycardia and nonspecific S-T and T-wave changes. Conventional studies of the cerebrospinal fluid gave normal results. No growth of organislns appeared in thirteen blood cultures, two urine cultures, one stool culture, one cerebrospinal fluid culture, and tracheal washings. The initial clinical impression \vas gram-negative bacteremia. Because of the tachypnea, hyperpnea, and fever, multiple pulmonary emboli and bacterial pneumonia were other diagnostic considerations, The elevated hcmatocrit value and history of recent vomiting suggested that the patient also was signilicantly dehydrated. Therapy instituted shortly after the patient’s admission consisted of physiologic saline, metaramino1 (Araminc), tetracycline, streptomycin, and penicillin. Within 4 hours, the blood pressure rose to 120/75 mm. Hg and use of the vasopressor was discontinued. During the first 2 hospital days, 12 1,. of physiologic saline and 3 L. of 5 per cent dextrose in water were administered intravenously, the total urine output being <3 I,. Twenty-four hours after admission, at a tilne when the patient had received 9 L. of fluid intravenously and had shown clinical improvement, her rectal temperature rose abruptly to 106.6’F. COW comitantly, her pulse rate increased to 160 regular beats per minute, her blood pressure rose to 160/100 mm. Hg, and her respiratory rate increased to 32 per minute. iI:et sponges were applied to the skin, and aspirin suppositories were administered. Promptlv
I60 I40 I20 ,~
PULSE Iboah/min.l
00
TEMPERATURE ( RECTAL-W
‘02
blwn.iig 1
WOOD PRESSURE
40 RESPIRATIONS t 1 min.)
32 24 I6
ANTIBIOTICS
Fig.
1. Pertinent
clinical
and
therapeutic
data.
HOSPITAL . -
DAY -
infection
151
the extract. Although the concentration rine in this pheochromocytoma was not high,* the tumor’s secretory potential is by the fact that the net amount of tissue epinephrine was ten to twenty times the
of epinephabnormally attested to containing normal.
Pheochromocytoma rn~q~u~rding
thereafter, her temperature fell to 98.6’F. A short time later, her blood pressure dropped to 120/70 mm. Hg, but her temperature rose again and remained elevated throughout the hospital course (Fig. 1 ). During the third hospital day, the patient’s abdomen rapidI>. became more distended. Examinzition revealed a large, tender, cystic mass in the right lower quadrant. Because plain abdominal roentgenograms and barium enema examination suggested cecal volvulus, celiotomy was performed early on the fourth hospital day. This procedure disclosed neither volvulus nor other mechanical obstruction. :In extremely dilated cecum was decompressed and fwe tears in its serosa were imbrirated. The surgeon stated that both kidneys and adrenal glands urere m)rmal to palpation. Although the patient withstood the entire procedure tvell, review of the operatic-e record showed that, during an apparently uneventful i~~duction of anesthesia with thiopental sodium, a transient rise in btood pressure from normotensive levels to 190/130 mm. Hg had been recorded. Postoperatively, the patient con&lued to exhibit fever, tachypnea, tachycardia, ilcus, and leukovytosis. Three dais after celiotomy, a Grade l/6 precordial systolic ejection murmur became audible for the first time. It was heard best at the left sternal border in the fourth intercostal space. LVithin 24 hours the murmur increased in intensity to Grade 3/6 and bacterial endocarditis was suspected. Therefore, large doses of penicillin and methicillin (Staphcillin) were administered, but the patient clied on the ninth hospital day. At nccr@sy, performed 6 hours after death, the only significant finding was an enlarged right adrenal gland weighing .50 grams. Its cut surface showed a gray-white meduliary tumor surrounded by cortical remnants. Part of the gland was covered with Zenker’s solution, aud the tumor in the medutla turned a mahogany color, indicating the presence of ca~echolamines.‘g Histologically, the cortex was normal and distinct from the adjacent neoplastic tissue. The tumor cells were pleomorphic and ranged ill size from 10 to 60~. Their cytoplasm was abundant and had uniformly fine granules which gaxre a positiw reaction to Gonwri’s chromaffin stain. Foci of hemorrhage and necrosis were present in the vascutar stroma. .An oil red 0 stain for neutral fat was positive in the cortex but not in the adjacent tumor. These histologic and histochemical lindings were considerecl to be typical of pheochromocytoma. The tumor \vas assayed biologically and chemically. Akid-saline tissue extracts were brought to concentrations of 0.1 mg., 0.5 mg., and 1.0 mg. of tissue per 0.2 ml. of solvent. The increase in arterial blood pressure of pithed rats was used as a measure 0r prebsor wtivitl,. ~lnkno~ns lvere assayed agaiust standards of 0.0001 mg., 0.0005 mg., and 0,001 mg. oi l-epincphrine. .4n cpincphrine content of 0.6 nag. per gram of tumor tissue was calculated in 3 six-point biologic assays. Chemical analysis of the tissue extract using ethylenediamine revealed a fluorescing reaction product identical in behavior to that of authentic l-epinephrine. The calculated concentration of this product, presumably epinephrine, was 0.6 mg. per gram of tumor tissue. No norepinephrine \vas found in
(1.~ovuwhelming
Discussion There is strong support for our belief that the tumor in this patient was responsible for the clinical features observed. First, the histoq; of hypertension2J and diabetes mellitus4 IS consistent with a functioning pheochromocytoma. Second, abdominal pain, nausea, and vomiting are frequent manifestations of this tumor.21 Third, a pronounced sensitivity to the hJ,potensive effects of phenothiazines has been observed in patients with this neoplasm.14,22 Fourth, patients larith pheochromocytoma are knobvn to exhibit various combinations of fever,2J spontaneous hypotension,15s24b25 tachycardia,26,27 tachypnea,g,28 flushed facies 11z14s\\reating,2s-s1 paralytic ileus,g,sZ and leu’kocytosis.8 Fifth, hypertension developed transiently during induction of anesthesia.33 Sixth, extensive antemortem investigation produced no proof of infection. Seventh, the pheochromoc>toma was the only significant finding at a carefully performed ne(‘ropsy. Finally, there is at least one other case of pheochromocytoma, strikingly similar to ours, in which the presenting manifestations initially. kvere attributed to ovcrwhelming infection. HamrinZ5 described an acutely ill, .54-year-old lvoman lvith epigastric cramps, vomiting, fever, tach>-cardia, leukoqtosis, azotemia, an elevated hemoglobin value, and a blood pressure of 130190 mm. Hg. Less than 2 days later, her temperature rose to 104.9’F., and she developed profound shock. The presumptive diagnosis was sepsis. After treatment with norepinephrine, hydrocortisone, and antibiotics, her clinical status promptI! improved. fluring the next 24 hours, 3,000 ml. of glucose and 4,000 ml. of saline solution \vcrc administered intravenously. Sut)sequently, a slightly tender mass, thought at first to represent a perinephric abscess,
152
Table
Fred,
Allred,
Gurber,
Retiene,
and Lipscomb
I. The effects of catecholanaines
on various
orgcln
systems ,in man
~ I
Epinephritle
Eject
1~ i Proposed ~ rereptw
i
Norepieephrine
Proposed receptor
.Tign
1 .Tign I
HearPJ’ Rate Strength of contraction output Blood pressureso,3’ .Systolic Diastolic Mean arterial pressure I’eripheral resistance (total) Respiration38 Rate Depth Miscellaneous Intestinal tonus3g Glycogenolysis?~ Calorigenic actions7 Leukocytes4o Sweat gland activity*’
kroreceptors 13
@
a and
[j
Hypotension
t
Tachypnea Hyperpnea
t t
Paralytic ileus IHyperglycemia Fever Leukocytosis Hyperhidrosis
1
Reflex
bradycardia
Systemic sion I’eripheral visceral
CY
hypertenand ischemia
Tachypnea Hyperpnea a and
p
Paralytic
ileus
*In the heart
was palpated in the upper region of her right kidney. Further studies showed that the mass was a pheochromocytoma which secreted epinephrine predominantly. The tumor was removed and the patient’s symptoms subsided. The features suggesting infection in Hamrin’s patient and in our patient can be attributed partly or entirely to epinephrine. In this regard, the receptor theory proposed by Ahlquist34 and modified by FurchgotV5 is helpful in understanding the systemic effects of epinephrine and norepinephrine. According to this theory, cells have specific receptors, possibly enzymes, that interact with a catecholamine to produce a given response (Table I). This classification proposes alpha (a) receptors for contraction of smooth muscle, beta (B) receptors for relaxation of smooth muscle and for increased rate and strength of cardiac contraction, and a combination of alpha and beta receptors for inhibition of contraction of intestinal smooth muscle.3g In general, norepinephrine stimulates alpha receptors, and epi-
nephrine stimulates beta receptors; however, each hormone activates both receptor sites to varying degrees. Some of the findings in the present case deserve special comment. The hypotension undoubtedly resulted from hypovolemia brought about by recurrent vomiting and sequestered fluid in the bowel lumen. There also may have been an extravasation of plasma into the interstitial space as a consequence of epinephrine-induced dilatation of precapillary vessels and constriction of postcapillary vessels. The patient’s subsequent toleration of massive replacement of fluid supports the contention that her intravascular compartment initially was contracted. Possibly, the phenothiazines aggravated the hypotension. Since these drugs block alpha receptor (vasoconstrictor) activity,4z the administration of them to a patient with a predominantly epinephrine-secreting pheochromocytoma would leave beta receptor (vasodilator) stimulation unopposed and shock could supervene. Mild elevations in body temperature are common in patients with pheochromo-
Pheochromocytonu~
cytoma,23 and temperatures as high as 107’F. have been cited in some cases.28,43 Epinephrine acts in two ways to elevate body temperature. It increases the production of heat by augmenting cellular metabolisnl,44 and it decreases the dissipation of heat by producing intense cutaneous vasoconstriction.45 Such vasoconstriction is ascribed to an effect of this hormone on alpha receptors. It is unlikely that a deficit in fluid volume per se was a major cause of fever in our patient, since she remained febrile after rehydration. The mechanism of the heart murmur reespecially since no mains speculative, cardiac abnormalities were disclosed at necropsy. Accounts have been recorded, however, of loud apical,gz46 pulmonic,15a22 or aortic46 systolic murmurs and/or soft, diastolicgr47 murmurs that appeared in patients with pheochromocytoma either during9,22 or shortly afteP symptomatic paroxysms. Necropsy in one of these cases9 and right heart catheterization and pulmonaq angiograms in anothe+ failed to reveal a cause for the murmur(s). Jlost pheochromocytomas secrete either norepinephrine or a combination of norepinephrine and epinephrine.J* In the latter circumstance, norepinephrine usually predominates.4g By contrast, pheochromocytomas secreting only epinephrine are rare.6o Since the content of cathecholamines in the adrenal gland may diminish rapidly after death,:l lve cannot exclude the possihility that the tumor in our patient also contained norepinephrine. Nevertheless, the results of the analysis are consistent with most of the clinical features observed. Summary
A patient is described who had fever, hypotension, tachypnea, hyperpnea, tachycardia, sweating, flushed facies, and leukocytosis. Her hypotension responded to the replacement of fluid, but the other clinical abnormalities persisted, and were accompanied later by paralytic ileus, higher fever, and the development of a precordial systolic ejection murmur of progressively greater intensity. The clinical impression initially was gram-negative l)acteremia, and, finally, bacterial endocarditis. Antemortem proof of infection, however, never was obtained. At necropsy,
musqueruding
us overwhelming
irl,fxtiotl
1.53
the only significant finding was an UIISLEpetted pheochromocytoma containing epinephrine. Evidence is presented to support the contention that the tumor was responsible for the clinical features 016erved.
1. 2.
3.
4.
De Courcy, J. L.: Pheochr(~tlloc~t~~tll~l, ~~III. J. Surg. 86:37, 19.53. Goldenberg, M., Serlin, I., Edwards, ‘I.., and Rapport, >T, Al.: Chemical screening method> for the diagno& of pheochromoc> kwa. I. Norepinephrine and epinephrine in h~tmat~ urine, .kn. J. Med. 16:310, 1954. Pahner, R. S., and Cas~leman, B.: I’araganglioma (chromaffinoma, ~~heochr(~Ill~~,t~)rll~j of the adrenA gland simul&~g malignant hywtension. Report of a case, Xe\v England J. &led. 219:793, 1938. Freedman, P., iUoulton, R., Rosenheim, M. l,., Soencer. Ak G.. and 11’iilowhb\,, 11. :I.: I’hwochromocytoma, diabetes, and glb-cosuria, (@Iart. J, Med. 27:307, 19S8. Futterweit, I\:., Allen, L,, alid kloher, AI.: I’heochromocytoma xvith radioactive iodine uptake and electrocardiographic abnormalities: Cze report with a review of thyroid-adrenal medullat->. interrelationships, ~Ietabolism 11 :S89, 1962. Crede, R. H., and Kerr, I\.. J,: l’heochromocytoma: Report of a case with qmptoms simulating acute a&et!atkwks. l’ostgrad. Med. 11:288, 19.52. Vkick, J. H.: F’h~~e~hro~~l(~!~to~ll~~ presenting as oostural hvootension. Proc. Ro! . SW. 1lcd. 57k73, 1964: ’ French, C., and Campagna, F. A\.: I’heochromoc\?oma with shock, marked letkocytosis, and unusual electrocardiograms Case repcort and review of the 1iterattn-e. ;\nn. lnt. 1Ied. 55:1.!7, 1961. JellilTe, R. S.: I’h~le~~chr(~l~lo~~totll~~ presentijlg as a cardiac al>d abdomi~l:~l catastrophe, Brit. ILI. J. 2:76, 1952. Gilliland, I. C., and l)xniel, 0.: I’haeochromoq,toma presenting as all abdominal emergent>-, Bit. 31. J. 2:275, 19.51. Leather, H. bI., Shaw, I). B., Gates, J. I<., alid lfTalker, 1~. WI. : Six cabes of ~h~~eochr~~~ll(~~~t(~~~~~~ with unusual clinical manifestations, 13rit. 11. J. 1:1373, 1962. l~ough~on, C. R.: I’h~~eochro~~~~~c~.to~l~~~ -Report of a case with interesting aspects, >Ied. J. A~uskalia 2:4?1, 1960. Peelen, J. iv., and De Groat, ~1.: I’heochromocvtoma complicated by prernancv, Ani. f. 0l)bt. ~.
.5*
6.
7.
a.
9.
10.
11.
12
13.
14.
15.
c>
.
.
1.54
16.
17. 18. 19. 20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
Fred, Allred, Gerber, Retiene, und Lipscomb
secreting phaeochromocy toma, lancet 2:904, 1961. Mortell, E. J., and IVhittle, J. I’.: Pheochromocytoma: Case report with certain observations on the pathologic physiolog>., J. Clin. Endocrinol. 5:396, 194.5. Sack, H., and Koll, J.: Cited by IIamrin.*~ McGill, R. J., and Davies, J. A H.: Phaeochromocytoma, Brit. M. J. 1:1698, 1962. Sherwin, R. I’.: Histopathology of pheochromocl-toma, Cancer 12:861, 1959. \.on Euler, lJ. S., Franksson, C., and Hellstrom, J. : Adrenaline and noradrenaline content of surgically removed human suprarenal glands, Acta Physiol. Scandinav. X:6, 19.54. Habermann, E. T., Millheiser, P. J., and Casten, D. F.: I’heochromocytomzi in the organ of Zuckerkandl presenting with gastrointestinal symptoms, J. Clin. Endocrinol. 24:334, 1964. Brady, I. A4.: Shock after administration of prochlorperazine in patient with pheochromocytoma. Report of a case with spontaneous tumor destruction, J..%.M.A. 169:1749, 1959. Smithwick, 1~. H., Greer, if:. E. R., Robertson, C. IV., and Wilkins, R. LfT.: Pheochromocytoma. :I discussion of symptoms, signs and procedures of diagnostic value, New England J. Med. 242:2S2, 1950. Ramsay, I. D., and Langlands, J. H. M.: Phaeochromocytoma with hypotension and polycythaemia, Iancet 2:126, 1962. Hamrin, B.: Sustained hypotension and shock due to an adrenaline-secreting phaeochromocvtoma, Lancet 2:123, 1962. Kahn, M. T., and Mullon, D. A.: Pheochromocytoma without hypertension. Report of a patient with acromegaly,, J..A.~l..X. 188:74, 1964. Davies, D. &I., Ross, J. H., Richardson, J. E., and Parry-Brown, A. I.: Experience lvith phaeochromocytoma, Postgrad. iX’Ied. J. 39:~?37, 1963. Belt, A. E., and Powell, T. 0.: Clinical manifestations of the chromaffin cell tumors arising from the suprarenal medulla. Suprarenal sympathetic syndrome, Surg. Gynec. & Obst. 59 :9, 1934. Kirkendall, if;. M., Liechty, R. I)., and C~ilp, I). A.: Diagnosis and treatment of patients with pheochromocytoma. Experiences at I~niversity Hospitals from 1941-1964, Arch. Int. ?VIed. 115:529, 1965. Delarue, N. C., and O’Brien, 11.: Pheochromocytoma: An important type of “curable” hypertension. A report of 11 cases and a review of the literature, Canad. J, Surg. 6:2.59, 1963. Gifford, R. W., Jr., Kvale, 1x7. F., Maher, F. T., Roth, G, M., and Priestley, J. T.: Clinical features, diagnosis and treatment of pheochromocytoma: A review of 76 cases, Proc. Mayo Clin. 39:281, 1964. Hughes, 1~. E., Bolt, D. E., and Hobson, Q. J. G.: Phaeochromocytoma: Presenting as resistant intestinal ileus, Proc. Roy. Sot. Med. 55:998, 1962. Crockett, K. A., Snow, E., and Rees, V. I~.: Pheochromocytomas as cause of unexpected
34. 35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
SO. Sl.
operating room deaths, A4m. Surg. 27:395, 1961. Ahlquist, 1~. P.: A study of the adrenotrophir receptors, Am. J. Physiol. X3:586, 1948. Furchgott, R. F.: The receptors for epinephrine and norepinephrine (adrenergic receptors), Pharmacol. Rev. llA29, 1959. Ginsburg, J., and Cobbold, A. F.: Effects of adrenaline, noradrenaline and isopropylnoradrenaline in man, itz \Volstenholme, G. E. \\‘., and O’Connor, M. : Ciba Foundation Symposium. Adrenergic mechanisms, Boston, 1960, little, Brown and Co., pp. 173-189. Inner, I. R., and Nickerson, b1.: Drugs acting on postganglionic adrenergic nerve endings and structures innervated by them (sympatho mimetic drugs), in Goodman and Gilman,‘* pp. 477-520. \\Thelan, R. F., aiid Young, I. \;I. : The effect of adrenaline and nor:idrenaline infusions on respiration in man, Brit. J. Pharmacol. 8:98, 19.53. Furchgott, 1~. F.: Receptors for sympathomimetic amines, ;n \~‘olstenhohne and O’Connor,‘~‘~ pp. 246-252. Samuels, A. J.: Primary and secondary leukoqte changes following the intramuscular injection of epinephrine hydrochloride, J. Clin. Invest. 30:941, 19Sl. IIermann, H., and Mornex, I~.: Human tumour~ secreting cathecholamines. Clinical and physiopathological study of the pheochromocytomas, translated hy R. Crawford, New York, 1964, The Macmillan Co., pp. 167.169. Goodman, I-. S., and Gilman, A.: The pharmaological basis of therapeutics, ed. 3, New York, 1965, The M~mnill~~~~ Co., p. 171. Howard, J. E., and Barker, \V. H.: Paroxy.smal hypertension and other clinical manifestations associated with benign chromaflin cell tumors Bull, Johns Hopkins (ph~le(~chr(~tll(~c~-t~Jlll~l), Hosp. 61:371, 1937. Swanson, H. E.: Interrelations betweeii thyroxin ;md adrenaline in the regulation of oxygen coiisumption in the albino rat, Endocrinology~ 59:217, 19S6. Engel, F. I>., LIencher, \V. H., and Engel, G. I,.: “Epinephrine shock” as a manifestation of ‘a pheochrolll~)c~t~~ln~~ of the adrenal medulla. Report of a case with surcessful removal of the tumor, .\m. ]. h1. SC. 204:649, 1942. Emanuel, I). .I.. Rowe, G. G., Musser, M. .I., and Philpot, V. B., Jr.: Proloiiged hypotension with fatal termination after a phentolamine (Regitine) methanesulfontate test, J.A.M.A. 16lA36, 1956. Bernal, I’.: Cited by Mackeith, R.: Adrenasympathetic syndrome. Chromaffin tissue tumour with paroxysmal hypertension, Brit. Heart J. 6:1, 1944. Goodall, McC., and Stone, C.: Adrenaline and noradrenaline producing tumors of the adrenal medulla and sympathetic nerves, Ann. Snrg. 151~~91, 1960. Van Euler, IJ. S., and Strom, G.: Present status of diagnosis and treatment of pheochromocy,loma, Circulation 15:5, 19.57. Hermanu and hIornex,4’ p. 130. Ibid., p. 1.37.