Technetium-99m-Labeled Red Blood Cellsin the Evaluation of Hemangiomas of the Liverin Infants and ChildrenJohn H. Miller

Division of Nuclear Radiology, Department of Radiology, Childrens Hospital of Los Angeles,and University of Southern California, School of Medicine, Los Angeles, California

The vascular origin lesions of the liver (capillary hemangioma/infantile hemangioendothelioma)that present in infancy or early childhood often have a typical clinical picture of hepatomegalyand congestive heart failure. These lesions rarely present as asymptomatic hepatomegaly,simulating a primary hepatic malignancy. These lesions may also simulate a primary orsecondary hepatic malignancy on cross-sectional imaging or angiography. Scintigraphicevaluations with technetium-99m-labeled red blood cells offers an accurate method of

identification of these lesions, and allows differentiation from other common primary orsecondary hepatic masses in infancy or childhood. This scintigraphic method may also beused to follow these patients after medical, radiation, or embolization therapy. Experiencewith seven patients with these tumors is reported and compared with eight children withother primary or secondary liver tumors also evaluated by this method.

J NucíMed 28:1412-1418,1987

H. i.emangiomatous lesions of the liver occurring ininfancy and childhood include capillary hemangiomaand infantile hemangioendothelioma (1-3). These tumors are histologically benign, but may cause intractable high output cardiac failure because of marked vascular shunting through the lesion (4). These lesionsmay be solitary or multiple throughout the entire liver(3,5). They may occasionally be mistaken for primaryor secondary malignant involvement of the liver (3,6,9). This is particularly true of those solitary mass lesionsthat present without an associated congestive heartfailure (3). It is of paramount importance to correctlyidentify these hemangiomatous lesions of the liver, asopen or closed biopsy of these lesions may lead touncontrolled hemorrhage and has been reported to befatal (10,11). Evaluation of these patients with techne-tium-99m- (99mTc)labeled red blood cells (RBC) allows

correct identification and accurate differentiation fromother benign or malignant lesions of the liver in child-

Received Aug. 22, 1986; revision accepted Mar. 25, 1987For reprints contact: John H. Miller, MD, Head, Div. of

Nuclear Radiology, Childrens Hospital of Los Angeles, 4650Sunset Blvd., Los Angeles, CA 90027.

Presented in part at the 9th Annual Western Regional ScientificProgram of the Society of Nuclear Medicine Meeting, Monterey,CA October 11-14, 1984.

hood. The utilization of [99mTc]RBCalso allows a rel

atively noninvasive method of sequential monitoringof these patients during courses of therapy includingtherapeutic embolization of these lesions (12).

MATERIALS AND METHODS

Fifteen children (nine males and six females) aged 2 daysto 8 yr presenting with hepatomegaly were evaluated with[99mTc]RBCs.Seven children had vascular origin lesions of

the liver, including three with multiple (infantile hemangioendothelioma) and four with solitary (capillary hemangioma)lesions. The three patients with multiple or multicentric lesions all presented with congestive heart failure and palpablehepatomegaly while the solitary lesions all presented as asymptomatic palpable abdominal masses or hepatomegaly. Theother lesions evaluated by this method include nodular hyper-plasia of the liver (four children), hepatoblastoma (one child),metastatic neuroblastoma (two children), and mesenchymalhamartoma (one child). All the nonhemangiomatous lesionswere proven by biopsy or surgical removal. The vascular originlesions were confirmed clinically. Twenty-six [99mTc]RBC

studies were conducted on this group of patients. In addition,there were 45 ultrasound (US) evaluations, 30 [99mTc]sulfurcolloid (SC) hepatic-splenic scintigraphic examinations, fivehepatobiliary studies utilizing [99mTc]iminodiacetic (IDA)

derivatives, three isotopie skeletal examinations, ten computed tomographic (CT) examinations with contrast enhance-

1412 Miller The Journal of Nuclear Medicine

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ment and 11 angiograms, performed. Two patients with he-mangiomatous liver lesions were evaluated with [""TcJRBCs

prior to and following angiographie embolization therapy.The patient's RBCs were labeled utilizing either an in vivo

or a modified in vitro method (13J4). A bolus of [""Te]

RBCs was administered with a dose of 0.280 mCi/kg to amaximum of 18.0 mCi. A three-phase technique was utilizedwith 3-sec dynamic scintigraphy immediately followed by apostinjection 300,000-count static scintiphoto to assess earlylabeled blood-pool activity within the lesion. After allowing aperiod of 10 to 20 min for equilibration, static 300,000-countscintiphotos of the liver were then acquired in various views.In every patient with a hemangioma, scintiphotos of the head,thorax, abdomen, and proximal extremities were obtained.

In all patients an anterior scintiphoto of the chest and upperabdomen was obtained in order to allow a direct comparisonbetween the [""Te] RBC within the cardiac chambers (heart

blood pool) and the hepatic lesions. The hepatic lesions,localized by reference to antecedent imaging ["TcJSC, US,

or CT) procedures, were compared to both the heart bloodpool and the surrounding uninvolved hepatic parenchyma toassess relative vascularity. Lesions were then identified asbeing equal to the heart blood pool, equal to the liver, orgreater than liver but less than the heart blood pool. Onlythose lesions that had ["TcJRBC activity equal to that of the

heart blood pool were considered to be hemangiomatouslesions of the liver.

RESULTS

The results of the initial evaluation of the 15childrenare given in Table 1. In all children with multiplevascular lesions (infantile hemangioendothelioma), perfusion of the lesions was identified on dynamic scintigraphy. On the immediate postinjection static blood-pool scintiphoto, activity persisted within the lesion andwas present on delayed static scintiphotos (Fig. 1) as

FIGURE 1Infantile hemangioendothelioma (Patient 2). Transverse anterior US (A)of the liver reveals multiple hypo-echoic masses (arrows) distributedthroughout both lobes of the liver.Anterior [""TcJSC static scintiphoto(B) reveals multiple focal voidsthroughout both lobes of the liver.Immediate anterior ["mTc]RBC post-

injection scintiphoto of the torso (C)reveals abnormally increased inho-mogeneous activity throughout theliver; heart (H), renal activity (R). Subsequent anterior static [""TcJRBCs

scintiphoto (D) reveals multiple focalareas equal in intensity to the heartblood pool (H). Correlation with the["TcjSC scintiphoto reveals thatareas devoid of activity (arrowheads)are now seen to have increased activity (arrowheads).

B

1414 Miller The Journal of Nuclear Medicine

''*

*

B CFIGURE 2Capillary hemangioma (Patient 6). Transverse US (A) reveals a solid mass arising from the left lobe of the liver (arrows)which is of less echogenicity than the immediately adjacent uninvolved hepatic parenchyma. Anterior ["mTc]RBCperfusion scintiphoto (B) reveals the presence of a hypervascular mass (arrows) in the left abdomen. Anterior ["Te]

RBC static scintiphoto (C) reveals a large vascular lesion (arrows) arising from the left lobe of the liver (L), with activityequal to the heart (H).

well. In all individuals with large solitary vascular lesions (capillary hemangioma) increased perfusion wasseen on dynamic scintigraphy. In all but one patient,activity was equal to the heart blood pool on the immediate postinjection static scintiphoto (Fig. 2). Allthese individuals had activity equal to the heart bloodpool on delayed static scintiphotos.

In two patients with hemangiomas who were evaluated with [99mTc]RBCs prior to and following angio

graphie embolization therapy, diminution of lesion size

was seen. In one patient, a large homogeneous lesionimmediately developed a large central photopenic defect (Fig. 3) that subsequently underwent involutionfollowing the embolization therapy.

In this group of patients with hemangiomas of theliver, there were no false-negative examinations norwere there any false-positive examinations. In other

words, no patients were encountered who had lesionswith activity equal to that of the heart blood pool ondelayed static scintiphotos who did not have heman-

B

FIGURE 3Capillary hemangioma treated by angiographie embolization therapy (Patient 5). Anterior [TcJRBC scintiphoto (A) reveals a vascular lesion(arrows) arising in the left lobe of theliver. Anterior [""TcJRBC scintiphoto

(B) following arterial embolizationnow reveals a large central photopenic defect (arrow) in the lesion.Subsequent examinations revealedcomplete absence of this lesion.

Volume 28 •Number 9 •September 1987 1415

giomatous lesions of the liver. In addition, no patientswith lesions who had activity less than that of the heartblood pool were subsequently shown to have heman-

giomas of the liver by other imaging modalities, surgicalspecimen, or autopsy. Evaluation of the patients withvascular lesions by CT (Patients 5 and 7) was lessvaluable as tumor could not be excluded on the basisof the CT findings. In the nonhemangioma group ofpatients, especially those with malignant disease, CTwas valuable in both identifying nature and extent ofthe liver lesion.

DISCUSSION

Previously, the diagnosis of a hemangioma of theliver in an infant or child was based on a combinationof imaging findings (6), especially scintiangiographyperformed at the time of administration of [WmTc]SC

(4,6J5). The characteristic findings were that of increased flow on dynamic scintigraphy and photopenicareas or voids within the liver parenchyma on delayedstatic scintiphotos. However, there was potential foroverlap of these scintigraphic findings with other lesionsthat have pronounced tumor vascularity and focal defects on the delayed [99mTc]SC scintiphotos (15,16).

Often, angiography was necessary for confirmation ofthe presence of a hemangiomatous lesion ( 74, / 7). However, there could be overlap of the angiographie appearance of these lesions with primary hepatic malignancies (17). Several patients (Patients 8, 11, 14, and15) who did not have hemangiomatous liver tumorsand were evaluated by [WmTc]RBC had lesions which

were seen to have increased perfusion on dynamicscintigraphy (Table 1). In none of these individuals,however, was activity seen in the lesion on either immediate postinjection or delayed static scintiphotos

equal to that of the heart blood pool. However, severalindividuals with lesions other than a hemangioma (Patients 8, 14, 15) did have lesions with increased [99mTc]

RBC activity as compared with the surrounding liverparenchyma, but none were equal to the heart bloodpool in activity. In every instance, these liver lesionswere clearly differentiated from those of hemangiomatous origin. This method allowed the accurate differentiation of capillary hemangioma/infantile heman-

gioendothelioma from those lesions that are the majordifferential concern in infants and children: hepatoblas-

toma, metastatic neuroblastoma, nodular hyperplasia(Fig. 4), and fibrovascular hamartoma. However, asbiopsy of the hemangiomatous lesions is contraindi-

cated, the distinction between the vascular origin lesionsis based on clinical presentation and imaging studies:multiple liver lesions associated with heart failure ininfantile hemangioendothelioma and a solitary liverlesion causing hepatomegaly in capillary hemangioma.

Based on this experience with hemangiomatous lesions of the liver in infants and children, it appears thatthese lesions have significantly different characteristicsfrom those previously reported in adult patients (18,21). The reported experience in adult patients is one ofa predominantly hypovascular process being seen ondynamic scintigraphy with only minimal to no activitybeing identified on the immediate postinjection staticscintiphoto but with appearance of considerable activityin the lesion within several hours. This delayed appearance in these lesions has been likened to the samephenomenon which may be observed on contrast enhanced CT in adult patients (22-25). A qualitative

difference between vascular origin tumors in infantsand children and those seen in adult patients is that ofclinical presentation. Adult lesions are never implicatedas a cause of congestive heart failure and are often

FIGURE 4Nodular hyperplasia (Patient 13). Anterior [99mTc]SC perfusion scinti

photo (A) reveals increased perfusionto a focal lesion (arrows) in the mid-portion of the liver. Anterior ["mTc]

RBC static scintiphoto (B) reveals anarea (arrows) of increased activity ascompared with the remainder of theliver. Activity in this region is greaterthan that of the surrounding liver butis not equal to that of the heart bloodpool. B

1416 The Journal of Nuclear Medicine

detected incidentally during the course of the evaluationof the liver for other reasons (11,18-25). Lesions inchildren also spontaneously regress and/or are responsive to steroid therapy in the majority of instances (4,12,16).

Evaluation of the liver utilizing [99mTc]RBChas a

number of advantages in the pediatrie patient. Thisprocedure is relatively noninvasive, there is virtually norisk of an untoward reaction, and in the majority ofinstances no patient sedation is required. This procedure has been well tolerated by patients and is wellaccepted by parents, who are often concerned by thetechnical aspects of angiographie evaluation of theselesions. This procedure can be performed on an outpatient basis and is well suited to sequential utilization.The total-body radiation dose is between 100 and 400mrad (0.020 rad/mCi) (26-28). Often this techniquehas been performed on critically ill patients utilizing aportable gamma camera. Also in those patients withcongestive heart failure, there is no risk of volumeoverload or contrast injury to hypoperfused kidneysfrom this procedure.

The initial evaluation of an infant or child presentingwith either clinical findings of a hemangiomatous liverlesion or asymptomatic hepatomegaly and/or a palpable upper abdominal mass should be with ultrasound(6,29). If the ultrasonographic appearance suggests thatof a hemangiomatous lesion (5), the next evaluationshould be with [99mTc]RBCs.When increased perfusion

and activity equal to the heart blood pool is identifiedin a liver lesion in a child indicating a hemangioma, nofurther evaluation is indicated as no other liver lesionhas this appearance. In the majority of patients, CT willnot be utilized as the combination of US and [99mTc]

RBCs in the appropriate clinical setting will be diagnostic.

REFERENCES

1. Landing BH. Tumors of the liver in childhood. In:Okuda K, Peter RL, eds. Hepatocellular carcinoma.New York: John Wiley and Sons, 1976: 205-206.

2. Witzlehen C. Liver. In: Rissane JM. Pathology ofinfancy and childhood. St. Louis: C. V. Mosby, 1975:267-308.

3. Dachman AH, Lichtenstein JE, Friedman AC, et al.Infantile hemangioendothelioma of the liver: a radio-logic-pathologic-clinical correlation. Am J Roentgenol1983; 140:1091-1096.

4. Stanley P, Gates GF, Eto RT, et al. Hepatic cavernoushemangiomas and hemangioendotheliomas in infancy. Am J Roentgenol 1977; 129:317-321.

5. Miller JH, Greenspan BS. Integrated imaging of hepatic tumors in childhood, part II: benign lesions(congenital, reparative, and inflammatory). Radiologv1985; 154:91-100.

6. Miller JH, Gates GF, Stanley P. The radiologie inves

tigation of hepatic tumors in childhood. Radiology1977; 124:451-458.

7. Kaude JV, Felman AH, Hawkins IF. Ultrasonographyin primary hepatic tumors in early childhood. FedRadial 1980; 9:77-83.

8. Mac Pherson RI, Saldana JA, Cone RM, et al. Primaryliver masses in infants. CañadAssoc Radial 1981;32:81-87.

9. Abramson SJ, Lack EE, Teel RL. Benign vasculartumors of the liver in infants: sonographic appearance.Am J Roentgenol 1982; 138:629-632.

10. Kassner EG, Friedman AP. Liver masses. In: HallerJO, Shkolnik A, eds. Clinics in diagnostic ultrasound:ultrasound in pediatrics. New York: Churchill Livingstone. 1981:80-97.

11. Kato M, Sugawara I, Okada A, et al. Hemangioma ofthe liver: diagnosis with combined use of laparoscopyand hepatic arteriography. Am J Surg 1975; 129:698-704.

12. Stanley P, Grinnell VS. Stanton RE, et al. Therapeuticembolization of infantile hepatic hemangioma withpolyvinyl alcohol. Am J Roentgenol 1983; 141:1047-1051.

13. Pavel DG, Zimmer AM, Patterson VN. In vitro labeling of red blood cells with Tc-99m: a new approachto blood pool visualization. J NucíMed 1977; 18:305-308.

14. Callahan RJ, Froelich JW, McKusick KA, et al. Amodified method for the in vivo labeling of red bloodcells with Tc-99m: concise communication. J NucíMed 1982; 23:315-318.

15. Gates GF, Miller JH, Stanley P. Scintiangiography ofhepatic masses in childhood. JAMA 1978; 239:2667-2670.

16. Sty JR, Starshak RJ, Miller JH. Gastrointestinal nuclear medicine. In: Sty JR, Starshak RJ, Miller JH.Pediatrie nuclear medicine. Norwalk: Appleton-Cen-tury-Crofts, 1983: 53-82.

17. Stanley P, Miller JH. Hepatic arteriography. In: Stanley P, Miller JH, eds. Pediatrie angiography. Baltimore: Williams and Wilkins. 1982: 179-213.

18. Good LI, Alavi A, Trotman BW, et al. Hepatic hemangiomas: pitfalls in scintigraphic detection. Gastro-enterology 1978; 74:752-758.

19. Engel MA, Marks DS, Sandier MA, et al. Differentiation of focal intrahepatic lesions with Tc-99m-RBCimaging. Radiology 1983; 146:777-782.

20. Rabinowitz SA, McKusick KA, Strauss HW. Tc-99mred blood cell scintigraphy in evaluating focal liverlesions. Am J Roentgenol 1984; 143:63-68.

21. Front D, Israel O, Groshard D, et al. Technetium-99m-labeled red blood cells imaging. Semin NucíMed1984; 14:226-250.

22. Freeny PC, Vimont TR, Barnett DC. Cavernous hemangioma of the liver: ultrasonography, arteriography, and computed tomography. Radiology 1979;132:143-148.

23. Itai Y, Furui S, Araki T, et al. Computed tomographyof cavernous hemangioma of the liver. Radiologv1980; 137:149-155.

24. Johnson CM, Sheedy PF, II, Stanson AW, et al. Computed tomography and angiography of cavernous hemangiomas of the liver. Radiologv 1981; 138:115-121.

25. Barnett PH, Zerhouni EA, White RI Jr., et al. Computed tomography in the diagnosis of cavernous hemangioma of the liver. Am J Roentgenol 1981;

Volume 28 •Number 9 •September 1987 1417

134:439-447. tion No. (FDA) 78-8044.26. Loevinger R, Bennan M. MIRO Pamphlet 1 (revised). 28. Srivastava SC, Chervu LR. Radionuclide labeled red

A revised scheme for calculating the absorbed dose of blood cells: current status and future prospects. Seminbiologically distributed radionuclides. New York: The NucíMed 1984; 14:68-82.Society of Nuclear Medicine, 1978. 29. Miller JH, Greenspan BS. Integrated imaging of he-

27. Kereiakes JG, Feller PA, Ascoli FI, et al. Pediatrie patic tumors in childhood, part I: malignant lesionsradiopharmaceutical dosimetry, 1976, HEW Publica- (primary and metastatic). Radiology 1985; 154:83-90.

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