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Pheochromocytoma masquerading as pre-eclamptic toxemia
Pheochromocytoma pre-eclamptic Current
concepts
MAHMOUD D.S.,
F.
masquerading
as
toxemia
of diagnosis
and treatment
EL-MINAWI,
M.D.,
D.G.O.,
M.CH.*
E.
PAULINO,
M.
CUESTA,
J.
CEBALLOS,
Cheverly,
M.D. M.D. M.D.
Maryland
A case of pheochromocytoma was presenting as pre-eclamptic toxemia superimposed on essential hypertension and was diagnosed during cesarean section. For more frequent reports and early diagnosis of pheochromocytoma associated with pregnancy, the following triad should be adopted: (1) The possibility of pheochromocytoma is to be kept in mind as a cause of hypertension in pregnancy; (2) routine quantitative estimation of 24 hour urinary excretion of 4-hydroxy-3-methoxy mandelic acid in toxemic and hypertensive patients; and (3) careful and gentle exploration of the abdomen in all laparotomies done for toxemic and hypertensive patients.
PHEOCHROMOCYTOMA WAS first reported by FrankelI in 1886, in a young girl with episodic hypertension. Since then, only 92 cases of pheochromocytoma with pregnancy have been reported in the world literature.37 7, 14, 21, 33, 3% 45, 469 43, 49 Because of
pregnancy is extremely hazardous to the mother and fetus; Fox and associates14 reported 43 maternal deaths out of 89 reported cases; one third of the cases were found at autopsy. This study demonstrates the importance of gentle exploration of the abdomen during laparotomies for hypertensive pregnant patients, advocates the routine quantitative measurement of 24 hour urinary excretion of 4-hydroxy-3-methoxy mandelic acid (VMA) in hypertension and toxemia of pregnancy, and discusses the current concepts of diagnosis and treatment of pheochromocytoma with pregnancy.
the close similarity between the clinical manifestations of toxemia of pregnancy and pheochromocytoma, the latter may masquerade as pre-eclampsia. Pheochrombcytoma with From the Departments of Obstetrics and Gynecology and of Surgery, Prince George’s General Hospital. *Present address: Ellis Fischel State Cancer Hospital and Cancer Research Center, Columbia, Missouri 65201. 389
390
El-Minawi
et al. Amer.
Case report S. M., a 32-year-old Negro woman, gravida 6, para 5, was admitted to Prince George’s General Hospital on l/10/70, for sustained hypertension and albuminuria. Her expected date of confinement was January 22, 1970. She was followed in the prenatal clinic for one month, when her blood pressure range was 160/120 to 160/l 10 until the day of admission when it was read at 210/120. The patient had headache, occasional excessive sweating, and huffy eyes, and her weight increased from 209 to 219 pounds in 4 weeks. The patient also had a urinary tract infection that was treated. Her past history revealed hypertensive episodes for the last 2 years. Her first 4 deliveries were normal, but her last one was complicated by hypertension. Physical examination. On admission to the hospital, the patient was well built, in no distress except for moderate headache. Her temperature was 98O F., pulse 90 per minute, respiration 22 per minute, and blood pressure 210/120. Examination of the head, ears, nose, and throat revealed no abnormal findings except buffy eyes. The lung fields were clear; the heart was not enlarged, and the sounds were normal. No murmurs were audible. The abdomen was not distended. The uterine enlargement was consistent with 36 week’s gestational size and was not irritable or tender. The viable fetus was palpable in breech presentation with regular heart sounds, 140 per minute. The cervix was soft, moderately effaced but undilated with intact membranes. There was mild pitting edema of the lower extremities. The neurologic examination elicited normal findings. The admitting diagnosis was essential hypertension with superimposed preeclamptic toxemia. Laboratory findings. On admission, the leukocyte count was 8,500 per cubic millimeter with 79 per cent polymorphonuclear leukocytes, 16 per cent lymphocytes, and 5 per cent bands. The packed cell volume was 45.5 per cent; and the hemoglobin, 15.2 Gm. Urinalysis showed a pH of 6, a specific gravity of 1,043, albumin 4+, and the reaction for sugar 2+. On microscopic examination, the urine was loaded with 10 to 12 white blood cells per high-power field (HPF) and 5 to 10 red blood cells per HPF. Blood chemistry studies gave the following values: sodium, 138 mEq., potassium 4 mEq., chloride 105 mEg., creatinine 1 mg. per cent, blood urea nitrogen 7 mg., and fasting blood sugar (FBS) 156 mg.
February J. Obstet.
1, 1971 Gynec.
per cent. The electrocardiogram showed sinus tachycardia and probably an old anteroseptal injury. Hospital course. The patient was at bed rest and was placed on a 1,500 calorie low-salt diet, chlorothiazide (diuril), and reserpine. For the first 3 days of admission, the blood pressure range was 160/100 to 180/110. The pulse rate range was 90 to 120 per minute. On l/13/70, it was decided to induce labor by oxytocin* drip that failed in the first attempt and was repeated 24 hours later without success. The remote possibility of pheochromocytoma was raised by that time. On l/15/70, cesarean section was performed together with bilateral tubal ligation. A living mature baby was delivered. The anesthetic agents used were methoxyfluoranet, NO,, and 0, inhalation. Gentle exploration of the abdominal cavity revealed a firm mass above the left kidney 3yz cm. in diameter, while the right side was essentially normal. The anesthesiologist reported fluctuations in the blood pressure from 180/110 to 200/120 with tachycardia during palpation of the mass. The clinical diagnosis of pheochromocytoma based on the physical findings and laparotomy was entertained. The postoperative course showed a blood pressure range from 160/110 to 200/160. The pulse rate ranged from 100 to 130. The vital signs were stable but with sustained hypertension. Investigations to confirm the diagnosis of pheochromocytoma were started on the eighth postoperative day. On l/23/70, her excretion of VMA was 22.2 mg. in 2,250 C.C. of total 24 hour urinary output, normal value, 0 to 10 mg. per 24 hr. The VMA level was high for 3 consecutive estimations 2 days apart. On l/30/70, the urinary catecholamine level was 578 mg. per 24 hr.; normal is less than 140. The 24 hour urine for metanephrine and nonmetanephrine determinations was 12 mg. per 24 hours. Meanwhile, the patient was prepared for surgery. Blood volume estimations on l/30/70 revealed a normal red cell volume (1,920) with the plasma overexpanded by 500 ml. (3,410). The patient received sodium pentobarbital,$ meperidine hydrochloride,§ and promethazine hydrochloride /I
*Pit&n, tPenthrane, SNembutal, $Demerol, /ISpaGe,
Parke, Davis & Co., Detroit, Michigan. Abbott Laboratories, North Chicago, Abbott Laboratories, North Chicago, Breon Labs., Inc., New York, New Wyeth Labs., Philadelphia, Pennsylvania.
Illinois. Illinois. York.
Volume Number
103 3
Pheochromocytoma
Fig. 1. Gross photograph
as preoperative medications. Phentolamine,* propanolol, and phenylephrine hydrochloride? were ready for use in the operating room. On 2/3/70, under methoxyfluorane, NO,, and inhalation anesthesia, resection of the 02 pheochromocytoma was performed through an upper transverse abdominal incision.zO* 2s At Pharm.
Products,
Winthrop
Labs.,
as toxemia
391
of the pheochromocytoma.
Fig. 2. Photomicrograph of the pheochromocytoma. The cells vary in size and shape, the cytoplasm is finely granular, and the nucleoli are prominent.
*Regitine, Ciba Jersey. tNeo-Synephrine,
masquerading
Inc., New
Summit, York,
New
New York.
one time during surgery, the pulse rate reached 150, but the patient’s condition improved after ligating the renal vein. After removal of the tumor, the blood pressure dropped to 110/80 and was controlled by phenylephrine hydrochloride. The arterial blood pressure and the central venous pressure were monitored throughout the operation. To maintain the blood volume, the patient received 2,000 C.C. of whole blood and 500 C.C. of Ringer’s lactate. The patient left the operating room in a good and stable condition. Postoperative period. The patient spent her first 2 postoperative days in the intensive care unit (ICU) where careful monitoring of the arterial pressure, central venous pressure, and electrocardiography were continuously observed. The central venous pressure range was 5 to 7 cm. of water. Her postoperative medications were meperidine hydrochloride, promethazine hydrochloride,* and promazine hydrochloride. The blood pressure was maintained in a range from 130/100 to 150/100. The blood chemistry studies revealed the following values: sodium 137 mEq., potassium 3.8 mEq., chloride 103 mEq., BUN 10, and FBS 246 mg. per cent. On 2/5/70, the VMA was 19.9 mg. in 3,400 ml. of total 24 hour urinary output. On 2/12/70, her 24 hour urinary excretion was only 1 mg. in 2,240 ml. of urinary *Phenergan,
Wyeth
Labs.,
Phiidelphia,
Pennsylvania.
392
El-Minawi
et al.
output. The patient was discharged on 2/15/70 with blood pressure 130/100 and FBS 185 to be followed in PGGH clinic. The pathology report indicated that the tumor weighed 25 grams and measured 4.5 by 4. by 3. cm. (Fig. 1). External surface was smooth and glistening. It was soft and rubbery in consistency, and the cut surface was reddish, hemorrhagic, and contained small cystic areas of degeneration in the center. Microscopically, the mass was well encapsulated and consisted of clumps of cells with irregular nuclei (Fig. 2) and eosinophilic cytoplasm. The histology was consistent with benign pheochromocytoma. There was a fine vascular network surrounding the clumps of cells, with no blood vessel invasion. Comment Although the incidence of pheochromocytoma has been reported to be 0.1 per cent in random autopsy,32 and 2.2 per cent in patients with idiopathic hypertension,ls only 92 cases of pheochromocytoma with pregnancy have been reported. The latter low incidence can be attributed to the presence of most tumors in patients in the fourth and sixth decade, to the fact that most cases are usually diagnosed as toxemia of pregnancy, and to the lack of alertness for this tumor between obstetricians. Pheochromocytomas may present with fluctuating hypertension associated with hyperg1ycemia,43 excessive perspiration or sustained hypertension, headache, epigastric pain, and blurring of vision that simulate and are difficult to distinguish from essential hypertension36 or toxemia of pregnancy.4Q Constipation, also a common association with both toxemia of pregnancy and pheochromocytoma, may result from the inhibitory effects of catecholamines on intestinal motility. Hyperglycemia is known to be associated with pheochromocytomazl 43 and occurs with greater frequency than expected in toxemia of pregnancy. The relation of obesity to pheochromocytoma is rather interesting and controversial. Although Danowskill mentioned that patients with pheochromocytoma are often thin and that pheochromocytoma and obesity are not often seen, our patient was obese, weighing 219 pounds. Obesity should
Amer.
February J. Obstet.
1, 1971 Gynec.
not be against the diagnosis of pheochromocytoma.2Q It is also of interest to mention, that in contrast to normal or underweight patients with pheochromocytoma, the overweight individuals are usually normotensive, but with superimposed paraxysms of hypertension.54 Routine blood examination may be a factor in suspecting pheochromocytoma in hypertensive pregnancy because pheochromocytoma may elaborate an erythrocyte-stimulating factor41 causing an absolute increase in red cell mass. In our case, the packed cell volume was 45.5 per cent and hemoglobin was 15.2 Gm. per cent, higher values than should be expected in toxemia of pregnancy. Diagnosis of pheochromocytoma is dependent on thinking of the possibility in the first place and on the physician’s awareness of the subtlety of its manifestations.31* 37 Although the diagnosis may be suspected from the family history+, 25, 34, 42~47 and physical examination, certain tests must be performed in order to confirm the initial impression. Also, the importance of exploration of the abdominal cavity in laparotomies on toxemic patients is illustrated in our case. All the abdominal cavity should be thoroughly but gently explored, because 80 per cent of all pheochromocytomas originate in the adrenal glands and 90 to 99 per cent of all tumors are located in the abdominal cavity.35l 41 Although a diagnosis may be made by pyelography, laminography, aortography,3R retroperitoneal injection of Co2, selective arteriography,26p 38 retrograde venography, and caval catheterization,23 all such techniques are risky,2T especially during pregnancy. I4 Pharmacologic testing with the use 15, 419 44 histafine,3% 34 or of phentolamine, tyramine is now less popular in face of the risksI 34 and because of the availability of the accurate measurement of the metabolites of catecholamines. As the major metabolites of norepinephrine and epinephrine are the metanephrine and VMA, the diagnosis of pheochromocytoma can be established by measurement of urinary catecholamines, metanephrine, normetanephrine, or VMA.I?* 34 A 24 hour urinary excretion of VMA is a cheap, reliable,
Volume Number
109 3
Pheochromocytoma
and technically easy screening test for pheochromocytoma during pregnancy. Steinwald and associates44 stated that, “In 80 to 90 per cent of the patients, the test will be sufficient to establish a diagnosis of pheochromocytoma.” If the test is negative and still there is a strong suspicion of the presence of the tumor, it can be repeated or the urinary catecholamines may be measured. Also, the ratio between the urinary epinephrine and norepinephrine patterns provides preoperative indication of the type of the tumor and its probable location. ** When the epinephriie values are high, the tumor is most likely to be in the adrenal gland. In contrast to adrenomedullary .tumors, the extramedullary pheochromocytomas secrete norepinephrine exclusively. 34 The routine use of VMA test may prove to be useful as a screening test in pregnancy. Data derived from the studies of Castren* and Jaffe and colleagues23 showed that the catecholamine excretion in pregnancy is within the range of normal for nonpregnant women. Also the toxemic patients studied by Castren* showed no striking abnormality in free catecholamine excretion. Management of pheochromocytoma in the first 5 months of pregnancy is based on the use of adrenergic blocking agents titrated against blood volume control and vasoconstrictors to be followed by surgery.14 In the latter months of pregnancy, it is preferred to control the blood pressure with blocking agents, allowing for fetal maturity and vaginal delivery. Cesarean section and removal of the tumor can be performed at the same time if there is adequate preoperative preparation.14 Operative removal of the tumor, in our case, was postponed to confirm the diagnosis, prepare the patient, and stabilize the hypertension episodes. The most widely used drug for preoperative preparation and management of such patients are the phenoxybenzamines.* Given orally in a single dose or twice daily doses totaling 40 to 100 mg. a day, phenoxybenzamine will produce a steady effect of normalization of the blood *Dibenzyline, Pennsylvania.
Smith,
Kline
& French
Labs.,
masquerading
as toxemia
393
pressure with freedom from hypertensive attacks.41 One should always keep in mind that the sudden suppression of the catecholamine effects by an alpha blocking agent such as phentolamine may produce sufficient hypotension to injure the fetus, which may already be compromised.ls Blood volume determination is essential as it does offer a control for assessing the return to normality and the need for preoperative intravascular volume expansion by administration of whole blood and fluids.6> 24* 4o The preoperative blood volume measurements of our patient showed a normal red cell volume with the plasma overexpanded by 500 ml. In fact, replacement or even overreplacement of the operative blood loss is important in preventing hypotension and operative death.41s 44 Preparations for a safe operation should include:. ( 1) insertion of an arterial cannula for continuous measurement of the arterial blood pressure, (2) insertion of a central venous pressure catheter to assist in evaluating adequate maintenance of blood volume, and (3) continuous electrocardiographic monitoring for early detection of possible arrhythmias and tachycardias. Propanolol, which should always be available, has been found useful in controlling the cardiac arrhythmias. There is a controversy in the world literature on the most safe and desirable anesthetic agent for operative removal of pheochromocytoma. 1v 24 We preferred to use methoxyfluorane anesthesia because of the greater stability of the cardiac rhythm and the reputed decrease of sensitivity of the myocardium to excesses of catecholamines.lO* I6 Halothane,* advocated by Cooper-man and co-workers9 and opposed by Brown,5 elicits little or no sympathetic activity but has a theoretical drawback of potentiating arrhythmias.44 Because many of these patients go into profound and prolonged hypotension after removal of the tumor,* spinal and epidural anesthesia are contraindicated. The use of ICU facilities for continuous monitoring of the blood pressure, central venous
Philadelphia, *Fluothane,
Ayerst
Labs.,
New
York,
New
York.
394
El-Minawi
pressure, and electrocardiography for 48 hours postoperatively should reduce the incidence of pheochromocytoma operative deaths and morbidity. The National Institutes of Health team for study of pheochromocytoma41stressedthe importance of following these patients with repeated urinary assaysbefore discharge from the hospital and at perhaps 6 month intervals for a few years. One should always remember that although operative removal
REFERENCES
1. 2.
3. 4. 5. 6. 7.
8. 9. 10. 11.
12.
13. 14.
25. 16. 17. 18. 19.
20.
February 1, 1971 Amer. J. Obstet. Gynec.
et al.
Apgar, V., and Papper, E. M.: Arch. Surg. 62: 634, 1951. Aubert, L., Pedimielli, P., Carcopino, C., Detolie, P., and Armand, P.: Sot. Med. Hop. Paris 40: 46, 1964. Becker, M. C., Bass, R. D., and Robin, C. N.: J. M. Sot. New Jersey 46: 339, 1949. Biskind, G. R., Meyer; M. A., and Beadner, S. A.: T. Clin. Endocr. 1: 113. 1941. Brown,“B. R.: Anesthesiology ‘11: 461, 1967. Brunjes, S., Johns, V. J., and Crane, M. G.: New Eng. J. Med. 262: 393, 1960. Calvy, G. L., Resnick, M. E., Knab, D. R., and Richardson, J. F.: J. A. M. A. 171: 151, 1959. Castren, 0.: Acta Phannacol. 20: Suppl. 2, 1963. Cooperman, L. H., Engelman, K., and Mann, P. E. G.: Anesthesiology 28: 575, 1967. Crout, J. R., and Broun, B. R.: Anesthesiology 30: 29, 1969. Danowski, T. S.: Clinical Endocrinology, Baltimore, 1962, vol. 4, The Williams & Wilkins Company, p. 364. Donath, A., Kaser, H., Ross, B., Ziegler, W., Octliker, 0.. Colombo. T. P.. and Bettex. M.: ’ Helv. Paediat. Acta i0; 1, 1965. Frankel, F.: Virchow. Arch, Path. Anat. 103: 244, 1886. Fox, L. P., Grandi, J., Johnson, A. H., Watrous, W. G., and Johnson, M. .T.: AMER. J. OBSTET. GYI&C. 164: 288, 1969. Gifford. R. W.. Roth. G. M.. and Kuvale. W. F.: j. A. M: A. 149: 1628,‘1952. ’ Glenn, F., and Mannix, H.: Ann. Surg. 167: 619, 1968. Goldenberg, M., Serlin, I., and Edwards, T.: Amer. J. Med. 16: 310, 1954. Goodall, McC., and Stone, C.: Ann. Surg. 151: 391, 1960. Griffin, W., Dilts, P. V., and Roddick, J. W.: Non-Obstetric Surgery During Pregnancy. Current problems in surgery, Chicago, 1969, Year Book Medical Publishers, Inc. Hume, D. H.: Amer. J. Surg. 99: 458, 1960.
of the pheochromocytoma cures all its reversible manifestations, hypertension and hyperglycemia may persist. Becausethe clinical manifestaions of pheochromocytoma are so variable in nature and extent and may simulate toxemia of pregnancy, we believe that measurement of a 24 hour urinary excretion of VMA should be a routine screening test in hypertension and toxemia of pregnancy.
21. 22. 23. 24. 25. 26. 27. 28.
29. 30. 31.
32. 33.
34.
35. 36. 37. 38. 39. 40. 41.
Hunt, A. B., and McConahey, W. M.: AMER. J. OBSTET. GYNEC. 66: 970. 1953. Hunter, R. B., Marshall, P. B., and Oram, F. J.: Quart. J. Med. 127: 225; 1963. Jaffe. R. B., Harrison. T. S.. and Cenrv. T. C.: AS& J. GBSTET. G~NEC. ‘104: 936, y9;9. Joas, T. A., and Craig, D.: J. A. M. A. 209: 927, 1969. Kelsall, A. R., and Ross, E. J.: Lancet 2: 273, 1955. Kohler, R., and Holsti, L. R.: Acta Radiol. (Diagn.) 4: 21, 1966. Koonce, D. H., Poolock, B. E., and Glassy, F. J.: Amer. Heart J. 44: 901, 1952. Kuale, W. F., Roth, G. M., Manger, W. M., and Priestly, J. T.: J. A. M. A. 164: 854, 1957. Lee, R. E., and Rousseau, P.: J. Clin. Endocr. 27: 1050, 1967. Maloney, J. M.: New Eng. J. Med. 233: 242, 1955. Melmon, K. L.: Catecholamines and the adrenal medulla, In Williams, R. H., editor: Endocrinology, ed. 4, Philadelphia, 1968, W. B. Saunders Comuanv. v. 379. Minno, A. M., Ben&t< W. A., and Kvale, W. F.: Mayo Clin. Proc. 30: 394, 1955. Moorhead, E. L., Caldwell, J. R., Kelly, A. R., and Morales, A. R.: J. A. M. A. 196: 1107, 1966. Packman, R. C., O’Neal, L. W., Wessler, S., and Avioli, L. V.: J. A. M. A. 212: 780, 1970. Page, L. B., and Copeland, R. B.: D. M. Jan., p. 1, 1968. Pratt, W. A.: .T. Clin. Endocr. 11: 630, 1951. Richards, P., - Adamson, A. R., and. MacDonald. G. 1.: Lancet 11: 820. 1969. Rossi, P., Kgufman, L., Ruzika, F. F., and Panke, W.: Radiology 86: 266, 1966. Saltz, N. J., Luttwartz, A., and Goldberg, G. M.: Ann. Surg. 144: 118, 1956. Schnelle, N., Ferris, D. O., and Schirger, A.: Anesth. Anala. 43: 641. 1964. Sjoerdsma, A., Engelman, K., Waldmann, T. A., Cooperman, L. H., and Hammond,
Volume 109 Number 3
42. 43. 44. 45.
W. G.: Ann. Intern. Med. 65: 1302, 1966. Smits, M., and Huizinga, J.: Acta Genet. 11: 137, 1961. Spargel, G., Bleicher, S. J,, and Ertel, N. H.: New Eng. J. Med. 278: 803, 1968. Steinwald, 0. P., Doolas, A., and Southwick, H. W.: Surg. Clin. N. Amer. 49: 87, 1969. Stutz, I. L., Rosenberg, S. A., Cohen, H. M., Chamovitz, R., and Bogarad, I.: Ann. Intern. Med. 47: 801, 1957.
Pheochromocytoma
46. Thiery,
47. 48. 49.
masquerading
as toxemia
395
M., Derom, R. H., Van Kets, H., De Schaepdryver, A. F., Bernard, P. J., Bekart, S. A. L., Hooft, C. M. J., Derom, F., Rally, G., and Roels, H. J. L.: AMER. J. OBSTET. GYNEC. 97: 21, 1967. Tisherman, S. E., Gregg, F. J., and Danowski, T. S.: J. A. M. A. 182: 152, 1962. Walker, R. M.: Brit. J. Surg. 51: 590, 1964. Wallace, L., and McCrary, J. D.: J. A. M. A. 157: 1404, 1955.
concepts
MAHMOUD D.S.,
F.
masquerading
as
toxemia
of diagnosis
and treatment
EL-MINAWI,
M.D.,
D.G.O.,
M.CH.*
E.
PAULINO,
M.
CUESTA,
J.
CEBALLOS,
Cheverly,
M.D. M.D. M.D.
Maryland
A case of pheochromocytoma was presenting as pre-eclamptic toxemia superimposed on essential hypertension and was diagnosed during cesarean section. For more frequent reports and early diagnosis of pheochromocytoma associated with pregnancy, the following triad should be adopted: (1) The possibility of pheochromocytoma is to be kept in mind as a cause of hypertension in pregnancy; (2) routine quantitative estimation of 24 hour urinary excretion of 4-hydroxy-3-methoxy mandelic acid in toxemic and hypertensive patients; and (3) careful and gentle exploration of the abdomen in all laparotomies done for toxemic and hypertensive patients.
PHEOCHROMOCYTOMA WAS first reported by FrankelI in 1886, in a young girl with episodic hypertension. Since then, only 92 cases of pheochromocytoma with pregnancy have been reported in the world literature.37 7, 14, 21, 33, 3% 45, 469 43, 49 Because of
pregnancy is extremely hazardous to the mother and fetus; Fox and associates14 reported 43 maternal deaths out of 89 reported cases; one third of the cases were found at autopsy. This study demonstrates the importance of gentle exploration of the abdomen during laparotomies for hypertensive pregnant patients, advocates the routine quantitative measurement of 24 hour urinary excretion of 4-hydroxy-3-methoxy mandelic acid (VMA) in hypertension and toxemia of pregnancy, and discusses the current concepts of diagnosis and treatment of pheochromocytoma with pregnancy.
the close similarity between the clinical manifestations of toxemia of pregnancy and pheochromocytoma, the latter may masquerade as pre-eclampsia. Pheochrombcytoma with From the Departments of Obstetrics and Gynecology and of Surgery, Prince George’s General Hospital. *Present address: Ellis Fischel State Cancer Hospital and Cancer Research Center, Columbia, Missouri 65201. 389
390
El-Minawi
et al. Amer.
Case report S. M., a 32-year-old Negro woman, gravida 6, para 5, was admitted to Prince George’s General Hospital on l/10/70, for sustained hypertension and albuminuria. Her expected date of confinement was January 22, 1970. She was followed in the prenatal clinic for one month, when her blood pressure range was 160/120 to 160/l 10 until the day of admission when it was read at 210/120. The patient had headache, occasional excessive sweating, and huffy eyes, and her weight increased from 209 to 219 pounds in 4 weeks. The patient also had a urinary tract infection that was treated. Her past history revealed hypertensive episodes for the last 2 years. Her first 4 deliveries were normal, but her last one was complicated by hypertension. Physical examination. On admission to the hospital, the patient was well built, in no distress except for moderate headache. Her temperature was 98O F., pulse 90 per minute, respiration 22 per minute, and blood pressure 210/120. Examination of the head, ears, nose, and throat revealed no abnormal findings except buffy eyes. The lung fields were clear; the heart was not enlarged, and the sounds were normal. No murmurs were audible. The abdomen was not distended. The uterine enlargement was consistent with 36 week’s gestational size and was not irritable or tender. The viable fetus was palpable in breech presentation with regular heart sounds, 140 per minute. The cervix was soft, moderately effaced but undilated with intact membranes. There was mild pitting edema of the lower extremities. The neurologic examination elicited normal findings. The admitting diagnosis was essential hypertension with superimposed preeclamptic toxemia. Laboratory findings. On admission, the leukocyte count was 8,500 per cubic millimeter with 79 per cent polymorphonuclear leukocytes, 16 per cent lymphocytes, and 5 per cent bands. The packed cell volume was 45.5 per cent; and the hemoglobin, 15.2 Gm. Urinalysis showed a pH of 6, a specific gravity of 1,043, albumin 4+, and the reaction for sugar 2+. On microscopic examination, the urine was loaded with 10 to 12 white blood cells per high-power field (HPF) and 5 to 10 red blood cells per HPF. Blood chemistry studies gave the following values: sodium, 138 mEq., potassium 4 mEq., chloride 105 mEg., creatinine 1 mg. per cent, blood urea nitrogen 7 mg., and fasting blood sugar (FBS) 156 mg.
February J. Obstet.
1, 1971 Gynec.
per cent. The electrocardiogram showed sinus tachycardia and probably an old anteroseptal injury. Hospital course. The patient was at bed rest and was placed on a 1,500 calorie low-salt diet, chlorothiazide (diuril), and reserpine. For the first 3 days of admission, the blood pressure range was 160/100 to 180/110. The pulse rate range was 90 to 120 per minute. On l/13/70, it was decided to induce labor by oxytocin* drip that failed in the first attempt and was repeated 24 hours later without success. The remote possibility of pheochromocytoma was raised by that time. On l/15/70, cesarean section was performed together with bilateral tubal ligation. A living mature baby was delivered. The anesthetic agents used were methoxyfluoranet, NO,, and 0, inhalation. Gentle exploration of the abdominal cavity revealed a firm mass above the left kidney 3yz cm. in diameter, while the right side was essentially normal. The anesthesiologist reported fluctuations in the blood pressure from 180/110 to 200/120 with tachycardia during palpation of the mass. The clinical diagnosis of pheochromocytoma based on the physical findings and laparotomy was entertained. The postoperative course showed a blood pressure range from 160/110 to 200/160. The pulse rate ranged from 100 to 130. The vital signs were stable but with sustained hypertension. Investigations to confirm the diagnosis of pheochromocytoma were started on the eighth postoperative day. On l/23/70, her excretion of VMA was 22.2 mg. in 2,250 C.C. of total 24 hour urinary output, normal value, 0 to 10 mg. per 24 hr. The VMA level was high for 3 consecutive estimations 2 days apart. On l/30/70, the urinary catecholamine level was 578 mg. per 24 hr.; normal is less than 140. The 24 hour urine for metanephrine and nonmetanephrine determinations was 12 mg. per 24 hours. Meanwhile, the patient was prepared for surgery. Blood volume estimations on l/30/70 revealed a normal red cell volume (1,920) with the plasma overexpanded by 500 ml. (3,410). The patient received sodium pentobarbital,$ meperidine hydrochloride,§ and promethazine hydrochloride /I
*Pit&n, tPenthrane, SNembutal, $Demerol, /ISpaGe,
Parke, Davis & Co., Detroit, Michigan. Abbott Laboratories, North Chicago, Abbott Laboratories, North Chicago, Breon Labs., Inc., New York, New Wyeth Labs., Philadelphia, Pennsylvania.
Illinois. Illinois. York.
Volume Number
103 3
Pheochromocytoma
Fig. 1. Gross photograph
as preoperative medications. Phentolamine,* propanolol, and phenylephrine hydrochloride? were ready for use in the operating room. On 2/3/70, under methoxyfluorane, NO,, and inhalation anesthesia, resection of the 02 pheochromocytoma was performed through an upper transverse abdominal incision.zO* 2s At Pharm.
Products,
Winthrop
Labs.,
as toxemia
391
of the pheochromocytoma.
Fig. 2. Photomicrograph of the pheochromocytoma. The cells vary in size and shape, the cytoplasm is finely granular, and the nucleoli are prominent.
*Regitine, Ciba Jersey. tNeo-Synephrine,
masquerading
Inc., New
Summit, York,
New
New York.
one time during surgery, the pulse rate reached 150, but the patient’s condition improved after ligating the renal vein. After removal of the tumor, the blood pressure dropped to 110/80 and was controlled by phenylephrine hydrochloride. The arterial blood pressure and the central venous pressure were monitored throughout the operation. To maintain the blood volume, the patient received 2,000 C.C. of whole blood and 500 C.C. of Ringer’s lactate. The patient left the operating room in a good and stable condition. Postoperative period. The patient spent her first 2 postoperative days in the intensive care unit (ICU) where careful monitoring of the arterial pressure, central venous pressure, and electrocardiography were continuously observed. The central venous pressure range was 5 to 7 cm. of water. Her postoperative medications were meperidine hydrochloride, promethazine hydrochloride,* and promazine hydrochloride. The blood pressure was maintained in a range from 130/100 to 150/100. The blood chemistry studies revealed the following values: sodium 137 mEq., potassium 3.8 mEq., chloride 103 mEq., BUN 10, and FBS 246 mg. per cent. On 2/5/70, the VMA was 19.9 mg. in 3,400 ml. of total 24 hour urinary output. On 2/12/70, her 24 hour urinary excretion was only 1 mg. in 2,240 ml. of urinary *Phenergan,
Wyeth
Labs.,
Phiidelphia,
Pennsylvania.
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et al.
output. The patient was discharged on 2/15/70 with blood pressure 130/100 and FBS 185 to be followed in PGGH clinic. The pathology report indicated that the tumor weighed 25 grams and measured 4.5 by 4. by 3. cm. (Fig. 1). External surface was smooth and glistening. It was soft and rubbery in consistency, and the cut surface was reddish, hemorrhagic, and contained small cystic areas of degeneration in the center. Microscopically, the mass was well encapsulated and consisted of clumps of cells with irregular nuclei (Fig. 2) and eosinophilic cytoplasm. The histology was consistent with benign pheochromocytoma. There was a fine vascular network surrounding the clumps of cells, with no blood vessel invasion. Comment Although the incidence of pheochromocytoma has been reported to be 0.1 per cent in random autopsy,32 and 2.2 per cent in patients with idiopathic hypertension,ls only 92 cases of pheochromocytoma with pregnancy have been reported. The latter low incidence can be attributed to the presence of most tumors in patients in the fourth and sixth decade, to the fact that most cases are usually diagnosed as toxemia of pregnancy, and to the lack of alertness for this tumor between obstetricians. Pheochromocytomas may present with fluctuating hypertension associated with hyperg1ycemia,43 excessive perspiration or sustained hypertension, headache, epigastric pain, and blurring of vision that simulate and are difficult to distinguish from essential hypertension36 or toxemia of pregnancy.4Q Constipation, also a common association with both toxemia of pregnancy and pheochromocytoma, may result from the inhibitory effects of catecholamines on intestinal motility. Hyperglycemia is known to be associated with pheochromocytomazl 43 and occurs with greater frequency than expected in toxemia of pregnancy. The relation of obesity to pheochromocytoma is rather interesting and controversial. Although Danowskill mentioned that patients with pheochromocytoma are often thin and that pheochromocytoma and obesity are not often seen, our patient was obese, weighing 219 pounds. Obesity should
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1, 1971 Gynec.
not be against the diagnosis of pheochromocytoma.2Q It is also of interest to mention, that in contrast to normal or underweight patients with pheochromocytoma, the overweight individuals are usually normotensive, but with superimposed paraxysms of hypertension.54 Routine blood examination may be a factor in suspecting pheochromocytoma in hypertensive pregnancy because pheochromocytoma may elaborate an erythrocyte-stimulating factor41 causing an absolute increase in red cell mass. In our case, the packed cell volume was 45.5 per cent and hemoglobin was 15.2 Gm. per cent, higher values than should be expected in toxemia of pregnancy. Diagnosis of pheochromocytoma is dependent on thinking of the possibility in the first place and on the physician’s awareness of the subtlety of its manifestations.31* 37 Although the diagnosis may be suspected from the family history+, 25, 34, 42~47 and physical examination, certain tests must be performed in order to confirm the initial impression. Also, the importance of exploration of the abdominal cavity in laparotomies on toxemic patients is illustrated in our case. All the abdominal cavity should be thoroughly but gently explored, because 80 per cent of all pheochromocytomas originate in the adrenal glands and 90 to 99 per cent of all tumors are located in the abdominal cavity.35l 41 Although a diagnosis may be made by pyelography, laminography, aortography,3R retroperitoneal injection of Co2, selective arteriography,26p 38 retrograde venography, and caval catheterization,23 all such techniques are risky,2T especially during pregnancy. I4 Pharmacologic testing with the use 15, 419 44 histafine,3% 34 or of phentolamine, tyramine is now less popular in face of the risksI 34 and because of the availability of the accurate measurement of the metabolites of catecholamines. As the major metabolites of norepinephrine and epinephrine are the metanephrine and VMA, the diagnosis of pheochromocytoma can be established by measurement of urinary catecholamines, metanephrine, normetanephrine, or VMA.I?* 34 A 24 hour urinary excretion of VMA is a cheap, reliable,
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and technically easy screening test for pheochromocytoma during pregnancy. Steinwald and associates44 stated that, “In 80 to 90 per cent of the patients, the test will be sufficient to establish a diagnosis of pheochromocytoma.” If the test is negative and still there is a strong suspicion of the presence of the tumor, it can be repeated or the urinary catecholamines may be measured. Also, the ratio between the urinary epinephrine and norepinephrine patterns provides preoperative indication of the type of the tumor and its probable location. ** When the epinephriie values are high, the tumor is most likely to be in the adrenal gland. In contrast to adrenomedullary .tumors, the extramedullary pheochromocytomas secrete norepinephrine exclusively. 34 The routine use of VMA test may prove to be useful as a screening test in pregnancy. Data derived from the studies of Castren* and Jaffe and colleagues23 showed that the catecholamine excretion in pregnancy is within the range of normal for nonpregnant women. Also the toxemic patients studied by Castren* showed no striking abnormality in free catecholamine excretion. Management of pheochromocytoma in the first 5 months of pregnancy is based on the use of adrenergic blocking agents titrated against blood volume control and vasoconstrictors to be followed by surgery.14 In the latter months of pregnancy, it is preferred to control the blood pressure with blocking agents, allowing for fetal maturity and vaginal delivery. Cesarean section and removal of the tumor can be performed at the same time if there is adequate preoperative preparation.14 Operative removal of the tumor, in our case, was postponed to confirm the diagnosis, prepare the patient, and stabilize the hypertension episodes. The most widely used drug for preoperative preparation and management of such patients are the phenoxybenzamines.* Given orally in a single dose or twice daily doses totaling 40 to 100 mg. a day, phenoxybenzamine will produce a steady effect of normalization of the blood *Dibenzyline, Pennsylvania.
Smith,
Kline
& French
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as toxemia
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pressure with freedom from hypertensive attacks.41 One should always keep in mind that the sudden suppression of the catecholamine effects by an alpha blocking agent such as phentolamine may produce sufficient hypotension to injure the fetus, which may already be compromised.ls Blood volume determination is essential as it does offer a control for assessing the return to normality and the need for preoperative intravascular volume expansion by administration of whole blood and fluids.6> 24* 4o The preoperative blood volume measurements of our patient showed a normal red cell volume with the plasma overexpanded by 500 ml. In fact, replacement or even overreplacement of the operative blood loss is important in preventing hypotension and operative death.41s 44 Preparations for a safe operation should include:. ( 1) insertion of an arterial cannula for continuous measurement of the arterial blood pressure, (2) insertion of a central venous pressure catheter to assist in evaluating adequate maintenance of blood volume, and (3) continuous electrocardiographic monitoring for early detection of possible arrhythmias and tachycardias. Propanolol, which should always be available, has been found useful in controlling the cardiac arrhythmias. There is a controversy in the world literature on the most safe and desirable anesthetic agent for operative removal of pheochromocytoma. 1v 24 We preferred to use methoxyfluorane anesthesia because of the greater stability of the cardiac rhythm and the reputed decrease of sensitivity of the myocardium to excesses of catecholamines.lO* I6 Halothane,* advocated by Cooper-man and co-workers9 and opposed by Brown,5 elicits little or no sympathetic activity but has a theoretical drawback of potentiating arrhythmias.44 Because many of these patients go into profound and prolonged hypotension after removal of the tumor,* spinal and epidural anesthesia are contraindicated. The use of ICU facilities for continuous monitoring of the blood pressure, central venous
Philadelphia, *Fluothane,
Ayerst
Labs.,
New
York,
New
York.
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pressure, and electrocardiography for 48 hours postoperatively should reduce the incidence of pheochromocytoma operative deaths and morbidity. The National Institutes of Health team for study of pheochromocytoma41stressedthe importance of following these patients with repeated urinary assaysbefore discharge from the hospital and at perhaps 6 month intervals for a few years. One should always remember that although operative removal
REFERENCES
1. 2.
3. 4. 5. 6. 7.
8. 9. 10. 11.
12.
13. 14.
25. 16. 17. 18. 19.
20.
February 1, 1971 Amer. J. Obstet. Gynec.
et al.
Apgar, V., and Papper, E. M.: Arch. Surg. 62: 634, 1951. Aubert, L., Pedimielli, P., Carcopino, C., Detolie, P., and Armand, P.: Sot. Med. Hop. Paris 40: 46, 1964. Becker, M. C., Bass, R. D., and Robin, C. N.: J. M. Sot. New Jersey 46: 339, 1949. Biskind, G. R., Meyer; M. A., and Beadner, S. A.: T. Clin. Endocr. 1: 113. 1941. Brown,“B. R.: Anesthesiology ‘11: 461, 1967. Brunjes, S., Johns, V. J., and Crane, M. G.: New Eng. J. Med. 262: 393, 1960. Calvy, G. L., Resnick, M. E., Knab, D. R., and Richardson, J. F.: J. A. M. A. 171: 151, 1959. Castren, 0.: Acta Phannacol. 20: Suppl. 2, 1963. Cooperman, L. H., Engelman, K., and Mann, P. E. G.: Anesthesiology 28: 575, 1967. Crout, J. R., and Broun, B. R.: Anesthesiology 30: 29, 1969. Danowski, T. S.: Clinical Endocrinology, Baltimore, 1962, vol. 4, The Williams & Wilkins Company, p. 364. Donath, A., Kaser, H., Ross, B., Ziegler, W., Octliker, 0.. Colombo. T. P.. and Bettex. M.: ’ Helv. Paediat. Acta i0; 1, 1965. Frankel, F.: Virchow. Arch, Path. Anat. 103: 244, 1886. Fox, L. P., Grandi, J., Johnson, A. H., Watrous, W. G., and Johnson, M. .T.: AMER. J. OBSTET. GYI&C. 164: 288, 1969. Gifford. R. W.. Roth. G. M.. and Kuvale. W. F.: j. A. M: A. 149: 1628,‘1952. ’ Glenn, F., and Mannix, H.: Ann. Surg. 167: 619, 1968. Goldenberg, M., Serlin, I., and Edwards, T.: Amer. J. Med. 16: 310, 1954. Goodall, McC., and Stone, C.: Ann. Surg. 151: 391, 1960. Griffin, W., Dilts, P. V., and Roddick, J. W.: Non-Obstetric Surgery During Pregnancy. Current problems in surgery, Chicago, 1969, Year Book Medical Publishers, Inc. Hume, D. H.: Amer. J. Surg. 99: 458, 1960.
of the pheochromocytoma cures all its reversible manifestations, hypertension and hyperglycemia may persist. Becausethe clinical manifestaions of pheochromocytoma are so variable in nature and extent and may simulate toxemia of pregnancy, we believe that measurement of a 24 hour urinary excretion of VMA should be a routine screening test in hypertension and toxemia of pregnancy.
21. 22. 23. 24. 25. 26. 27. 28.
29. 30. 31.
32. 33.
34.
35. 36. 37. 38. 39. 40. 41.
Hunt, A. B., and McConahey, W. M.: AMER. J. OBSTET. GYNEC. 66: 970. 1953. Hunter, R. B., Marshall, P. B., and Oram, F. J.: Quart. J. Med. 127: 225; 1963. Jaffe. R. B., Harrison. T. S.. and Cenrv. T. C.: AS& J. GBSTET. G~NEC. ‘104: 936, y9;9. Joas, T. A., and Craig, D.: J. A. M. A. 209: 927, 1969. Kelsall, A. R., and Ross, E. J.: Lancet 2: 273, 1955. Kohler, R., and Holsti, L. R.: Acta Radiol. (Diagn.) 4: 21, 1966. Koonce, D. H., Poolock, B. E., and Glassy, F. J.: Amer. Heart J. 44: 901, 1952. Kuale, W. F., Roth, G. M., Manger, W. M., and Priestly, J. T.: J. A. M. A. 164: 854, 1957. Lee, R. E., and Rousseau, P.: J. Clin. Endocr. 27: 1050, 1967. Maloney, J. M.: New Eng. J. Med. 233: 242, 1955. Melmon, K. L.: Catecholamines and the adrenal medulla, In Williams, R. H., editor: Endocrinology, ed. 4, Philadelphia, 1968, W. B. Saunders Comuanv. v. 379. Minno, A. M., Ben&t< W. A., and Kvale, W. F.: Mayo Clin. Proc. 30: 394, 1955. Moorhead, E. L., Caldwell, J. R., Kelly, A. R., and Morales, A. R.: J. A. M. A. 196: 1107, 1966. Packman, R. C., O’Neal, L. W., Wessler, S., and Avioli, L. V.: J. A. M. A. 212: 780, 1970. Page, L. B., and Copeland, R. B.: D. M. Jan., p. 1, 1968. Pratt, W. A.: .T. Clin. Endocr. 11: 630, 1951. Richards, P., - Adamson, A. R., and. MacDonald. G. 1.: Lancet 11: 820. 1969. Rossi, P., Kgufman, L., Ruzika, F. F., and Panke, W.: Radiology 86: 266, 1966. Saltz, N. J., Luttwartz, A., and Goldberg, G. M.: Ann. Surg. 144: 118, 1956. Schnelle, N., Ferris, D. O., and Schirger, A.: Anesth. Anala. 43: 641. 1964. Sjoerdsma, A., Engelman, K., Waldmann, T. A., Cooperman, L. H., and Hammond,
Volume 109 Number 3
42. 43. 44. 45.
W. G.: Ann. Intern. Med. 65: 1302, 1966. Smits, M., and Huizinga, J.: Acta Genet. 11: 137, 1961. Spargel, G., Bleicher, S. J,, and Ertel, N. H.: New Eng. J. Med. 278: 803, 1968. Steinwald, 0. P., Doolas, A., and Southwick, H. W.: Surg. Clin. N. Amer. 49: 87, 1969. Stutz, I. L., Rosenberg, S. A., Cohen, H. M., Chamovitz, R., and Bogarad, I.: Ann. Intern. Med. 47: 801, 1957.
Pheochromocytoma
46. Thiery,
47. 48. 49.
masquerading
as toxemia
395
M., Derom, R. H., Van Kets, H., De Schaepdryver, A. F., Bernard, P. J., Bekart, S. A. L., Hooft, C. M. J., Derom, F., Rally, G., and Roels, H. J. L.: AMER. J. OBSTET. GYNEC. 97: 21, 1967. Tisherman, S. E., Gregg, F. J., and Danowski, T. S.: J. A. M. A. 182: 152, 1962. Walker, R. M.: Brit. J. Surg. 51: 590, 1964. Wallace, L., and McCrary, J. D.: J. A. M. A. 157: 1404, 1955.