Preoperative localization of pheochromocytoma

T h e ] o u r n a l of P E D I A T R I C S

711

Preoperative localization of pbeocbromocytoma Several tests are available which indicate pheochromocytoma as a probable cause of hypertension. Measures [or localization of the tumor(s) are, however, less effective. Preoperative localization is relatively more important in children than in adults since there is a higher incidence of multiple tumors in the younger age group and such tumors are often located at some distance from the adrenal glands. A previously described technique [or localizing tumors in which plasma samples obtained by catheterization of several veins are analyzed for catecholamine has been modified. Seven previously undetected pheochromocytomas were localized by this modified method in a boy from whom 5 tumors had been surgically removed at an earlier date.

Daniel S. Fleisher, M.D., ~ Gerardo Voci, M.D., Samuel L. Cresson, M.D., and

Lester Karafin, M.D. PHILADELPHIA~ WITH

THE

PA.

TECHNICAL

ASSISTANCE

M u c H of the difficulty in establishing the diagnosis of pheochromocytoma has been eliminated by the development of the Regifine test and by improved methods for the determination of urinary catecholamines and 3-methoxy, 4-hydroxymandelic acid ( V M A ) . Extensive efforts to localize the tumor(s) in adults prior to surgical exploration of the adrenal areas do not seem justified since in 86 per cent of a large series of cases only a single tumor was present within one adrenal gland?, 2 By contrast, in 32 per cent of 100

OF

Benjamin Mehlman, M . S . * *

cases in children the tumors were multiple and both intra- and extra-adrenal in location. 1 In only 49 per cent of the cases in c h i l d r e n was the tumor single and located within the adrenal gland? Preoperative localization of the tumor(s), therefore, can assume considerable importance in children. It is the purpose of this communication to describe a recent experience with the problem of localization and to present a modification of a previously described localizing technique? CASE REPORT

From the Departments of Pediatrics, Surgery, and Urology o[ Temple University School of Medicine at St. Christopher's Hospital for Children, 2600 North Lawrence Street, Philadelphia, Pa. ~'Address, St. Christopher's Hospital ]or Children, 2600 N. Lawrence Street, Philadelphia, Pa. 19133. ~Divls~on of Bioehemlstry, Walter Reed Army Institute o[ Research.

C. T., a 10-year-old white boy, was admitted to St. Christopher's Hospital for Children on March 26, 1962, for evaluation of a congenital heart defect. He had been well until two months prior to this admission when he developed fever, cough, and dyspnea. He was admitted to another hospital and gradually improved after receiving

7 12

Fleisher et al.

May 1964

C.T. IOYEAR OLD WHITE MALE I

HOSPITAL W621500 5/4/62

=(

D

C

l

A B C D NORMAL

NOR-EPINEPHRINE I EPINEPHRINE (MICROGRAMS PER LITER) 9.9 0.5 ] 9.8 0.2 12,3 0.5 12.3 O.T 4.0

0.|

Fig. 1. Plasma catecholamine levels. The lettered points represent the location of the catheter tip when blood samples were obtained. Note the identical values for norepinephrine content from C and D. We were unable to localize tumor tissue which could account for the two highest norepinephrine levels being in the inferior and superior vena cava just o u t s i d e the right atrium. antibiotics, digitalis, and other supportive therapy. Marked cardiomegaly w a s demonstrated and a changing high-pitched murmur was heard. Blood pressure recordings in his arms ranged from 138/94 to 160/124. On admission to our hospital he was alert and in no acute distress. Blood pressure was 160/105 in the upper extremities and 180/130 in the lower extremities. Grade 3 retinopathy was noted as evidenced by resolving exudates at the macula, Grade 3 arterial narrowing and sclerosis, numerous absorbing edematous residues in the maculopapular bundle area, and numerous choroidal infarcts. A Grade 3 "sea gull" systolic cardiac m u r m u r was audible. Diastole was clear. A prominent cardiac thrust was noted. The cardiac rate was 132 per minute. The liver was palpable 1 cm. below the right costal margin. The remainder of the physical examination was within normal limits. Roentgenograms of the chest revealed cardiomegaly, almost selectively due to left ventricular enlargement. The electrocardiogram revealed a

myocardial strain pattern, normal axis deviation, and severe left ventricular hypertrophy. O n March 31, 1962, a dose of 2.5 mg. of Regitine was administered intravenously and produced a fall of blood pressure of 50 mm. Hg systolic and 48 mm. H g diastolic. O n April 4, 1962, the test was repeated using 1 mg. of Regitine with similar fall of blood pressure of 42 mm. Hg systolic and 36 mm. Hg diastolic. The responses to the Regitine injections were considered abnormal and suggested the diagnosis of pheochromocytoma. The urinary excretion of 3-methoxy, 4-hydroxymandelic acid ( V M A ) was increased in each of 2 twenty-four hour collections. The values were 21 and 19.8 mg. per 24 hours, respectively. The normal value is less than 6.8 rag. per 24 hours. Roentgenograms following retroperitoneal insufttation of pure carbon dioxide we{e suggestive of an adrenal mass on the right side but did not delineate the left side very well. O n April 13, 1962, exploratory surgery was performed through a transverse abdominal incision following several preoperative intramuscular r c.~ ,og~LoL&w,~,L~ ..LE

NOR-EPINEPHRINE "T EPINEPHRINE (MIGROGRAMSPER LITER) A t5.6 3.4 B 9.5 1.4 C 7.o t.5 D 7.7 t.6 E IL9 2.8 NORMALI 4.0 0.1

Fig. 2. Plasma catecholamine levels. The letters represent the locations at which blood samples were obtained for the respective eatecholamine levels. Residual tumor tissue was believed to be intra-abdomlnal in location and was presumably draining into the azygos vein in addition to the inferior vena cava to account for the observed norepinephrine levels.

Volume 64 Number 5

Localization of pheochromocytoma

su~(m~a

abnormal on 10 separate occasions (range 6.8 to 19.3 mg. per 24 hours). Postoperative blood pressure recordings also were elevated. O n May 4, 1962, an attempt was made to localize residual tumor tissue by means of the technique described by von Euler and colIeagues. 4 Blood samples (Fig. 1) were obtained from: (1) the inferior vena cava distal to the renal veins, (2) the inferior vena cava proximal to the renal veins, (3) the inferior vena cava immediately outside the right atrium, and (4) the superior vena cava adjacent to the right atrium. A modification of the method of Weil-Mahlerbe and Bone s, 6 was employed for the catecholamine determinations. The high concentrations of norepinephrine in comparison to those of epinephrine suggested that residual tumor tissue was located outside of the adrenal gland. T h e two highest levels of norepinephrine were identical in the blood specimens from the inferior vena cava and from the superior vena cava (3 and 4). The location of residual tumor tissue remained unknown because of our inability to account for the venous drainage of the tumor tissue emptying into both the inferior and superior vena cava. A modification of this technique was devised and carried out on May 18, 1962 (Fig. 2). Blood samples were obtained from: (1) the azygos vein at the level of the diaphragm; (2) the azygos vein near the point where it emptied into the vena cava; (3) and (4) the right and left in-

suTt*Y~

2o

VMA 15 (.O/t4~)

o Q o

9 NORM*LRt.~(

~

9

9

9

9

7 13

t

Fig. 3. Blood pressures during second surgical exploration. Systolic blood pressures are represented by the upper circles and diastolic pressures by the lower circles. Note the marked fall in blood pressure levels as the final three tumors were removed. No norepinephrine was administered subsequently because the blood pressure became stabilized.

administrations of Regitine in individual doses of 2.5 rag. The areas in and around the kidneys, mesentery, aorta, and urinary bladder appeared to be free of tumor tissue. A tumor 1.5 cm. in diameter was removed from the right adrenal gland along with approximately three-fourths of the gland. The extirpation of 3 nodules in the left adrenal necessitated almost complete removal of the gland. A fifth nodule was removed from the right periadrenal area. The anesthetist's record indicated no sustained fall in blood pressure during the entire operative procedure. Postoperatively urinary V M A excretion was

[

200

C.T. IOYEAR OLD WHITE MALE 1 HOSPITAL P~621500 5128162

(MM Hg)

80

40

t

9 o

| 30

t

60

t |t

tttt

| 90

~ 120

| 150

ttt

t

t

@ 180

210

240

@ 270

300

MINUTES

( ~ INTU CATION ~ ) SURGERY BEGUN (~ MANIPULATION OF TUMORS ON RIGHT (~) MANIPULATION OF TUMORS ON LEFT ~)~(~ REMOVAL OF THREE TUMORS FROM RIGHT PERI-AORENAL AREA REMOVAL OF FOUR TUMORS FROM LEFT PERt-ADRENAL AREA ~ SURGERY ENDED EXTUBATION

Fig. 4. Urinary VMA excretion. Note that all values prior to the second operation were abnormal and that all values following the second operation have been normal.

7 14

Fleisher et al.

nominate veins, respectively; and (5) the inferior vena cava proximal to the renal veins. The norepinephrine concentration was highest in the specimen from the lower part of the azygos vein; the next highest value was in the specimen from the inferior vend cava. It was reasoned that residual tumor tissue was located intra-abdominally and that a portion of the blood draining the area(s) of tumor tissue entered the azygos vein via the deep lumbar veins and another portion entered the inferior vend cava by some other route. The administration of Regitine orally (100 mg. daily in divided doses) was begun on May 19, 1962. On May 28, 1962, a second surgical exploration was undertaken. Four small tumors were found and removed from the left periadrenal area, and 3 additional ones, the largest of which was 1 inch in diameter, were removed from the right periadrenal area. The blood pressure fell to 80/60 during the removal of these latter three tumors, rose to 100/70, and remained at this level (Fig. 3). Histologically, the tumor tissue was compatible with pheochromocytoma. Some elements resembling neuroblastoma were noted in a few areas. No decision as to the benign or malignant nature of the tumor tissue could be made. During the first 8 postoperative hours, the patient's blood pressure rose gradually to 160/120 and remained at that level. The possibility was considered that this hypertension might have been the result of the large doses of hydrocortisone which were being administered intravenously. Three days later the dose of hydrocortisone was reduced to 50 mg. per day. The patient's blood pressure fell promptly to normal levels and has remained there for the past year. All determinations of urinary excretion of VMA following the second operation have been within normal limits (Fig. 4). VMA excretion rates were normal in the patient's parents and in his two siblings. Full activity was gradually achieved and the patient has remained in excellent health to the present time (1 year since the operation). His electrocardiogram has become normal, and serial roentgenograms of the chest reveal a progressive decrease in cardiac size. Digitalis was discontinued 2 weeks after the second operation. He continued to receive 10 mg. of hydrocortisone daily until February, 1963, when the drug was discontinued to test his residual adrenal function. The results of this test were equivocal and will be repeated.

May 1964

DISCUSSION

Because of the significantly higher incidence of multiple tumors in children, x, 2 the need for precise localization procedures preoperatively is relatively greater than in adults. Extra-adrenal pheochromocytomas have been reported in such diverse locations as the ureter7 renal capsule, s urinary bladder, 9 organ of Zuckerkandl, 1~ thorax, 1~ neck, 11 and intracranially. 12 Unfortunately, intravenous and retrograde pyelography, roentgenograms following retroperitoneal CO2 insufltation, and aortography often do not precisely identify or localize single tumors reliably. W h e n there are multiple a n d / o r extra-adrenal tumors the probability of identifying alI of them is even less. I n a search for a more precise method of localization, von Euler and co-authors ~ in 1955 devised a technique based on determinations of catecholamines in blood samples obtained at various points along the inferior vend cava. It was assumed that the location from which the blood sample with the highest level of catecholamine content was drawn would indicate the location of the functioning pheochromocytoma. I n 1957, they modified the technique to include a sample of blood from the superior vend cava at the point of entrance of the azygos vein? Since the azygos vein is formed in the abdomen by the union of the deep lumbar veins, this modification is important when dealing with retroperitoneal tumors whose blood supply could drain into the deep lumbar veins. T h e azygos vein, however, also drains some areas of the thorax. Hence, even the modified technique of von Euler in certain instances could not differentiate whether functioning pheochromocytoma tissue was in the abdomen or in the thorax. Consequently, we have modified the technique to include blood specimens from the upper and lower portions of the azygos vein. (Subsequently, one of us (G. V.) has passed a catheter into the azygos vein in the course of several routine cardiac catheterizations and has encountered no difficulty.) I n order to lateralize a possible cervical or intracranial tumor, we propose that samples of blood be

Volume 64 Number 5

taken from veins draining each side of the neck (right and left innominate veins). With the further addition of blood samples from the inferior vena cava, sufficient information should be available to localize functioning pheochromocytoma tissue in the abdomen, thorax, or neck. F r o m the surgical standpoint this is usually sufficient preoperative information. Crout and Sjoerdsma is have utilized the technique of von Euler 4 in several instances and found it to be of value. T h e y list the following indications for its use: (1) when previous surgical exploration was not curative; (2) to determine whether a known extra-abdominal tumor is functional; (3) in a desperate situation when a patient might not survive an exploration which might fail to reveal the tumor; and (4) when the tumor functions continuously and produces solely norepinephrine and no epinephrine. T h e smooth preoperative, operative, and postoperative course in o ~ n t may have been due in large part to the preoperative therapy with Regitine. 1~ This case offers further support to the dictum that the removal of all functioning pheochromocytoma tissue should result in an immediate fall in blood pressure during the operation. I n view of the hereditary aspects of pheochromocytoma, 1~ we plan to repeat the measurements of the V M A excretion of the patient's parents and siblings at periodic intervals. SUMMARY

The case of a 10-year-old boy with 12 pheochromocytoma tumors is presented. At the first operation only 5 tumors were observed and removed. A modification of a technique devised by von Euler is described for the localization of functioning pheochromocytoma tissue in the abdomen, thorax, or neck. By utilizing this modification in our patient, data were obtained which indicated an intra-abdominal location of residual tumor tissue. Previously, the unmodified technique had yielded data insufficient to localize the tumors. T h e removal of 7 additional intra-abdomlnal tumors at a second opera-

Localization of pheochromocytoma

7 15

lion confirmed the interpretation of the results of the modified localizing technique. T h e patient has made an apparently complete clinical a n d biochemical recovery.

We wish to thank the Waiter Reed Army Research Institute, Division of Biochemistry, for the plasma catecholamine determinations and F. William Sunderman, Jr., M.D., for suggesting von Euler's technique.

REFERENCES

1. Melicow, M. M., and Uson, A. C.: Pheochromocytoma in adults and children. Exhibit at the clinical congress of the American College of Surgeons, Atlantic City, N. J., October 14 to 19, 1962. 2. Robinson, M. J., and Williams, A.: Clinical and pathological details of two cases of pheochromocytoma in childhood, Arch. Dis. Childhood 31: 69, 1956. 3. yon Euler, U. S., and Strom, G.: Present status of diagnosis and treatment of pheochromocytoma, Circulation 15: 5, 1957. 4. yon Euler, U. S., Gemzell, C. A., Strom, G., and Westman, A.: Report of a case of pheochromocytoma with special regard to preoperative diagnostic problems, Acta reed. scandinav. 153: 127, 1955. 5. Weil-Mahlerbe, H., and Bone, A. D.: Chemical estimation of adrenaline-like substances in blood, Biochem. J., 51: 311, 1952. 6. Weil-Mahlerbe, H., and Bone, A. D.: Adrenergic amines of human blood, Lancet 1: 974, 1953. 7. Harlem, O. K.: Pheochromocytoma with secondary pyelonephritis, J. PEDIAT. 57: 225, 1960. 8. Pengelly, C. D. R.: Pheochromocytoma within the renal capsule, Brit. M. J. 2: 477, 1960. 9. Scott, W. W., and Eversole, S. L.: Pheochromoeytoma of the urinary bladder, J. Urol. 83: 656, 1960. 10. Cone, T. E., Jr., Allen, M. S., and Pearson, H. A.: Pheochromocytoma in children. Report of three familial cases in two unrelated families, Pediatrics, 19" 44, 1957. 11. Cone, T. E., Jr.: Recurrent pheochromocytoma. Report of a case in a previously treated child, Pediatrics 21: 994, 1958. 12. Cahill, G. F.: Pheochromocytoma. J. A. M. A. 133: 180, 1948. 13. Crout, J. R., and Sjoerdsma, A.: Catecholamines in the localization of pheochromocytoma, Circulation 22: 516, 1960. 14. Insley, J., and Smallwood, W. C.: Pheochromocytoma in children, Arch. Dis. Childhood 37: 606, 1962.