, : ~ . ~ .

~4 Junie 19n S . - A . M L I) 1 E <; I· T y () <; " R I F

more impllrt :lncc to success in infant cardiac s urgery than is Ihe met hod llf ca rdiopulmonarv bypass employed. In thi s rel! :,rd . it should be :,dded that there is far less room for err-or in the Infa nt than there is in the c hild or :,dult. :l nd that mini:,ture equipment and instruments can be very helpful.

Finally. tWll things in parti c ular ha ve proved ve r y useful in dealinl! w ith these infants . Firstl y. :,rtificlal \'entdatlon with war;;'ed :I nd humidified oxygen - air mi x tures not only prevents chest complications and helps (0 deal with pneu ­moni a. but h:,s enabled us 10 maint :, in nllrm :.! blllJ\ t.:mperatures pustLlperativelv a lmost without exception . Secondly. intr:,ve nous isopre naline is in~aluable post­llperatively as it prevents metabolic acidosis. by increasing cardiac llutpUt :,nd by causing peripheral vasodilatation.

CONCLUSION

We h;I\'e b\!e n gratified by llur measure of success In primary surgica l closure llf ve ntricul:,r septal defect In

infants . and prov ided that correction is c:,refuily performed a nd co mplete . we consider this to be the procedure of choice in dealing with infants Whll fai l to respond tll medical man age ment.

We should like to th ank our colleagues at Groote Schuur Hospital a nd Red Cross War Memorial Children 's Hospital for help with these cases: M r R , P. Hewllson and Dr M. S. Barnard. who o perated upon some of these cases: and M ,ss M. Emerson fo r secretari al ass istance. We also wish to thank Dr J . G . Burger. Superintendent of Groote Sc huur Hospital. for permission to publish : and the So uth Afflca n Co unc il lor Scientific and Industrial Research and the Cltv Council " I Cape Town for financial support.

REF ER ENCES I . Keilh. J . 0 ., Rowe , R . O. 3nd Vi all . P . tl ~~X ) : H t'urt Di.\ ('flw '-n

Jllfmrc,Y (Inti C hildhood . New York : Macmill an . , Ca rtmill . T . B . . DuShane . J . W ., McGoo n. D . C . ilnd Kirklin. J . 'lA'

(1~&6) : J. Thor~c . CarJi{p .. ;}~c , Su rg .. 52 . 4Kb . J. Hotfman . J . I. E . anJ Rudol ph . A. . M . f l lJn~ , : Ame r . J . Ca rd ,nl., lb .

fi J4 . .I Murrlm-. A . G . ;Ind Hr:.J\lI1w;Jld . I\i . \ . ( l~(1) : Ci rcul:.J t ill l1 , l~ . J-l .. 5. Mustard . W . T . JJ1d Tru!iilcr . G . A . lIlJ61) : Cana J . J . Sun; .. ..& . J.'~ fl . H a llm::ln. (j , L.. Cooley . O . A . anJ Hillodwt:ll . R . U . ,ll,Ihnl'

Thor3c . Ca rd lClY3sc . Sur~ .. S2 . 410. I . Sigm an . J . "'1 . . Stern. A . M . and SIO;IIl. H . r. . 11 4n7, : PcJI ;lIri..::s. JI1 .

~ .

Liver Transplantation in Biliary Atresia with Concomitant Hepatoma *

JOHAN \ .-\N WYK~. C G. HALGRIMSON. G. GILES. J. LILLY. G. MARTINEAU. ANI) T. E. STARZL. /)ep(lflillelll oJ SlIrgerr . U lli' 'I.'r .l'ifr of Colorudo School of Medicil1e and DI'/H'er V I'terlll/.l· Admillistratioll

/10.lp illfl , Ol'l/\'l'f , Colorado . USA

SUMMARY

Two cases are reported in which the very infrequently reported association was found of liver cell carcinoma and biliary cirrhosis secondary to congenita l biliary atresia. A search of the literature revealed 4 previous reports of cases with similar pathology. Our 2 patients were both operated upon within the first few months of life, at which time congenital biliary atresia was documented, and in 1 instance temporarily corrected. They ran a progressive downhill course until they both received replacement livers, one at 4 years of age and the other at 12. at which times hepatoma was fOtlnd in the excised cirrhotic liver • . One patient is in good health 18 months post­transplantation. The other developed metastases but died of gUtro-intestinal bleeding and pneumonia 76 days post­transplantation.

s . . ~ f ro MI'd . J . ~6 . xx~ I 1'172 ).

Congenital biliary atresia ranks high in the candidacy list for hepatic tra nsplanta tion . and constitutes the single most frequent indication for liver replacement in a series re ­ported from o ur institution ." In 2 patie nt s treated in this manner. hepatoma was present in the cirrhotic livers. exc ised at the time of transplantation . The diagnos is of hepatoma had been made pre-operat ivelv in I instance. but in the other the finding of a tum o ur in the specimen was a surprise.

The occurrence of primary liver cell carcinoma in livers with pre-exis ting cirrhosis due to congenital biliary atresia is unusual. Absolon first mentioned thi s association in :, report on thor:lcic duct lymph drainage for bile duct :lIresia .' Three cases were subsequently reported by Oku­\,:lma .-~ Fis h"' and Deoras.' . This communication reports o n the 2 :,bo\'c-mentioncu cases of congenital biliary atresia ~' ith cnnc(lmitant hepa­toma tre:l ted by hepatic replacement.

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CASE REPORTS

Case

,"" 12-vear-old l!irl was ;IIJmilled to the Universitv of Coloradl; Medical~ Centre in May 1909. with a histor'y of rersistent jaundice. which had started in the neonatal period, At an exploratory laparotomy shortly after birth. ;, choledochoduodenostomy was performed for congenital biliary altresia of the correctable type. She was relativelv ,ymptomfree during the 10 years that followed but de­\'eloped severe upper gastro-intestinal bleeding from oeso­phageal varices in 1906. for whieh a meso-caval shunt was performed . Her subsequent clinical course indicated ;, ,lowly progressive Jeterioration. With fluctuation between mild asymptomatic Jaundice and severe exacerbation, ;,ssoci;lted with malabsorption. liver and spleen enlargement ;md bilirubin levels of up to 35 mgjlOO ml. A liver biopsy in early 1967 showed marked parenchymal bile stasis with ;,bsence of bile in the large ducts.

A hepatic arteriogram I Fig. I). inferior ven;, cavagralll ;, nd technetium scan of the liver ;;howed what appeared to be a large tumour in the right lobe of the liver. which was highly suspicious of a hepatoma. At operation ,)n II May 1969. a liver replacement procedure was done ;,nd the mesocaval shunt was ligated . The immediate post­,'perative course was unco~plicated and normal liver function. as measured by serum protein levels. bilirubin . transaminase. alkaline phospha tase and liver .;cans. re­m;,ined .; .. tisfactorv for 2 weeks after operation

Fig. I. Hepatic arteriogram. Case 1. showing large intra­hepalic lumor mass in the right lobe.

An occlusion of the left renal vein. secondary to throlll­bosis of the ligated meso-caval shunt, caused a transient loss of left renal function . This complication resolved spontaneously . After an episode of hepatic rejection had

bl!en successfullv tr~ateJ. the tf:ln "pl;,nteJ li,,::r underwent ;, seconJ rejection which was accomp;tnled by ,evere gastro_ intestinal bleeding episodes. The patient died on 20 Julv 1909 . with terminal bronchopneumonia and respiratory insutiiciencli, A small nodule had appeared on chest X-rav in the upper lobe of the left lung approximately 2 week's prior to hl!r death I Fig. 21. This was interpreted as ;, pulmonarv metastasis from th~ pre-existing hepatoma.

Fig. 2. Tomogram showing a small melaslalic nodule in Ihe upper lobe of the left lung. case I .

Alp~a-feto-p,roteins which have pro\en III b~ of a diag­nostic " and prognostic ' value in cases of li\cr-cell carci­noma ,\ere ele\'ated befllre tr;,nspl ;,nl;!lion ;ln J Juring th.: ;n days of .. urvival.

Pathological findings: Recipient's o\\n li\er weigheJ 2025 g and appeared diffusely but une\enly nodular. On ~ection . it contained a 10 x 10 x 8 cm grey . streaked. encapsulated mass in the middle of the right lobe. Several ~maller masses 3 - 12 mm in diameter were found in the capsule of the right lobe. The vasc ulature was normal. but the common bile duct could not be identified.

Microscopically the lobul a r pattern was distorted b\ broad and thin bands of dense fibrous connective tissue. There was an absence of normal bile ducts in many portal regions but in some there were prolifer:lled bile ducts peri-

24 Junie 1972 S.-A. MEDtES[ TYDsh:RtF ~87

pherally There W;I.' lymphatic ,md histiocytic Infiltration of the portal zones ,IS well as periportal and pericentral bile stasis (Fig. :I)

The large tumour m;lss was ;1 well-differentiated hep;ltOm ,l. There was a disorganized pattern of liver cords and s inu­,oids without a lobular pattern and portal zones. The nuclei were h y perchroma tic and a few rare mitoses were noted (Fig -ll. The subcapsular nodules showed a similar :Ippearance excepl for the nuclear changes .

~ig_ 3. Photomicrograph of the cirrhotic changes in the liver with extra hepatic biliary atresia. case I.

The transplanted liver weighed I 300 g and was soft. thbby and reddish-brown . On the cut surface a thick white nuid. apparently from the duct system. was exuding from ·n;lny points.

\1icroscopically the lobula r pattern \\";I~ preserved. Th.: nlcrstitium was lledematous and contained mononuclear

: ~I.I' Minimal bile duct proliferation was seen. and all . c hepatocytes showed severe damage with foamy cyto­~I~sm and degenerate nuclei. Reticulin-staining showed neal collapse and there was much bile stasis.

EVidence of cytomegalo virus involvement was wide­' Ne<1d throughout the ga stro-intestinal tract and elsewhere .

.\ four-vear-old lurl Was first admitted to the Univcrsil\.' ·f C •

. olorado Medical Centre on 22 Llnuary I 47(). Five

weeks after a normal birth . an exploratory laparotomy and operative cholangiogram at another hospital showed .. n uncorrectable biliarY atresia . .\ liver biops\ ,howed pOrt ,!i fibrosis. bile duct prolifa:l tion and bile stasis. During her tirst 3 years of life. she bled on several occasions from oesophageal \·arices :!nd de\·eloped gross ascites. An ortho­topic hepatic homotransplantation and splenectomy were carried out on the day of admission to our centre . The postoperati\e course W;J5 uncomplicated. and the liver function tests returned lU normal le\els shortly after operation. The pati.:nt is in good health at the time nf writing. IS O1l)nth, r<"t .t r:, n<plantatinn.

Fig. 4. Pholomicrogr.lpb of a section of the hepatoma in case I.

Alpha-feto-protein \\:1, pre,ent in the p;llIent"s serum al the time of op.:ration but disappeared after ;1 few monlh, (Fig. 51 . The tindings In [hi, ,:lse have been reported b\ Alpert e/ af.'·

Pathological findings: Re.:ipient"s own liver weighed I 080 g. On examination the liver had ~ dark green lobula ted capsule and a J;ti"k green cut surface. marked b y soft nodule,; delineat~J b\ white-gre\ firm strands of [issue. There \\as ;.1,,) " : - . 18 mm \\ hite-vellow 'Ofl nodule present.

On micfl),cllpic .:.\amin~ti<)n there \\·a, p,eudolobuic form<1tion. the duc" \\ere absent to scant\. but bile duc­tules were increased ;It the edges of the pseudolobule, There was bile sta,;i,; In the parench\·mal and Kuptfer cells :In(\ bile c;,nali\.·uli.

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The histological oiagnllses were bile ouct :t1resia. biliarv .:irrhosis :Ind hepatoma,

.TRANSPLANTATION 7

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DISCUSSION

Environmental factors such as the presence of aflatoxin ;Ind cycasin \C,' are strongly suspected in the aetiology of primary liver carcinoma in the adult. The frequency with which cirrhosis of various causes is associated with hepa­lorna varies greatly on a geographical basis." For instance. I he incidence of hepatoma in certain parIS of Africa is much higher than the incidence of cirrhosis."" '" whereas liver carcinoma usually develops in longstanding. slowly­progressing cirrhosis in the European."

It has been claimed by Edmondson' and Ishak and Glunz" that in those parts of the world where the frequencv "f hepatic carcinoma in adults is high. there is a strange ;,bsence of reported cases in children, Howeler. Prates"' reported Ihat hepatoma occur,,,; quite commonly among children in Mozambique. where the same disease is .:ndemic in adults, Reports by Watanabe from Japan." Pang from China." Benson from South Africa.' Lin from Formosa' ;,nd Hoe from Vietnam," have also questioned the assess­ment by Edmondson and Ishak t'I al.

Whatever the merits of the foregoing general contro­lersy. it does seem clear that hepatoma in infants and children with underlying cirrhosis has not been frequently r.:poned , In a survey of the literature by Jones'" in 19()O.

unly 7 patients out of 12~ h;lo clrcinoma coincidental With cirrhosis. Other reports by Graser. ,,' Clatworthy· and Bigelow ' indicate a similar low incidence of pre-existing oisease. Fraumeni" carried out an epidemiological ~tUdy

"n hepatoma in childhood in the United States. and re­ported on 282 patients. of whom only 5 had pre-existing liver disease. In other reports"" of hepatoma. as~ociated liver pathology has included giant-cell hepatitis and cirr­hosis of several causes,

In the reported cases of hepatoma associated with biliar\ atresia."; '"'''' as well as in our own 2 cases. the initiatio~ of oncogenesis is not understood. However. a reasonable hypothesis may be that of the triggering mechanism of liver injury. with repair and regeneration as put forwaru by Gal!." So far all hepatomas in biliary atresia have been ;Issociated with the extra hepatic variety of atresia. but have never occurred in the intrahepatic atresia victims, who tend to live much longer. On these grounds. one may speculate that the bile accumulation and stasis that is so prominent in the extrahepatic but not the intrahepatic type. is a major factor in irritation. scarring. and finallv neoplasia, In our own cases. both children were subjected to laparotomy at an early stage with no suspicion of the presence of tumour. Since the natural course of hepatom~ in children is a rapidly progressive and fatal one.' " it seem, obvious that the tumours in these patients must have developed in the months prior to transplantation. The presence of the tumour was known in advance in case I. but in case 2. it was a completely unexpected finding.

Primary hepatic malignancy without metastases, which could not be treated by conventional subtotal liver re­section. was originally considered to be the most unequi­local indication for orthotopic liver transplantation, This position has changed drastically with the observation that most patients with such extensive hepatomas developed recurrent neoplasm from which they eventually died. even after successful liver replacement," Of the 2 recipienh reported in this article. patient I illustrates the nature of the problem. Although death occurred from other causes. the development of metastases ' had already resulted in a hopeless prognosis in less than 3 months. In contrast. patient 2 was the exception to prove the rule. She is still well and tumour-free 18 months after liver replacement. apparently cured of an early hepatic malignancy, The out­come in this case is an argument in bvour of the liver replacement procedure for presumed benign hepatic disease. instead of the alternate operation of :luxiliary hepatic transplantation which would have unknowingly left the maligl1ftnt process in place,

The meticulou,s care of patients lI'ith cung.::nit:tI biliary dtresia and the prolongation of their liles. :tnd thus their cirrhotic process. in order to hale them treated by hepatic transplantation. may lead to :1 more frequent association of hepatoma and cirrhosis in the patient with bile duct :Itresia,

Aided by research grants from the Veterans Administration . by grants RR-00051 . and RR-00069 from the General Clinical Re:;earch Centers Program of the Division of Research Re­'\ources. National Institutes of Health and by grants A[-10176-01. AI-AM·08898, AM-0777!. GM-OIA86. HE-09110 of the l 'nited States Public Health Service.

24 Junie 1972 S.-A. MEDIESE TYDSKRIF 889

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Fig. 6. Appearance of the excised liver of case 2. Hepatoma indicated by arrows.

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S. ~, M . E ., Slanl, T . E .. Schur, P . H . and Isselbacher, K. J . ~ ... ~: Gastroenterology , 1 an the press). '" D, R . P . (1958): S . Afr . Med. J .. 32, 845 .

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10. Flhhcn8ton D .C. ' Armed F urce. lnSlitu(e of Pathol opy. II. F" , J . C . and McCarv, R . G . ( 1966): Arch . Surg ., 93 . 355.

r,urnem . J . F . jnr <l9bM) : J . Nat. Cancer InS[ .. 40 . 1087.

12. Gall. E. A . in Schiff . L .. ed. (1960) : OiseoJts of 'he tiver. 2nd ed., p. 702. Philadelphia : 1. B. Lippincott Co.

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phia : W . B. Saunders Co. 26. Sc<iner. P . E. (196(l) : Cancer (Philad .). 13. 108S . 27 . Sieiner. P . E .. Camain. R. and Nelik. J . (19)91: Cancer Res .. 19. 567. 28 . Watanabe . H . and Kobayashi . T. (1961) : Keio J . Med .. 10. lSI.

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