Carr, B

Iwatsuki, S

Kakizoe, S

Selby, R

Sheahan, DG

Starzl, TE

Todo, S

Tzakis, AG

Yokoyama, I

English

Name not available

Clinicopathologic factors affecting patient survival and tumor recurrence after orthotopic liver transplantation for hepatocellular carcinoma

D-Scholarship@Pitt

l J . i • ! i l 1 ! , I I .1 -I! -I: : ~ ! 1 i Clinicopathologic Factors Affecting Patient Survival and Tumor Recurrence After Orthotopic Liver Transplantation for Hepatocellular Carcinoma I. Yokoyama, D.G. Sheahan, B. Carr, S. Kakizoe, R. Selby, A.G. Tzakis, S. Todo, S. Iwatsuki, and T.E. Starzl THE role and value of orthotopic liver transplantation (OLTx) in the treatment of primary hepatic malignan-cies have been debated because of high tumor recurrence rates.l-I Certain clinicopathologic entities have been shown to influence patient survival rates for hepatocellular carcinoma (HCC).3.4 In the current study, we analyzed various histopathologic features in the livers of 106 liver transplant recipients with HCC for their influence on patient outcome. PATIENTS METHODS During the period from January 1980 to December 1989. 106 (6%) of a total of 1.786 patients underwent OLTx because of the presence of HCC. They received cyc!osporine-steroid combina-tion therapy for their basic immunosuppression. Chemotherapy was given to many of the pauents during the postoperative period, but the treatment was not based on a uniform protocol. The inftuence of the following risk factors was assessed: (I) tumor size, (2) tumor number. 131 shape of the tumor Icircum-scribed or infiltrative), (4) tumor distribution within the liver juni-or bilobar). (5) pseudocapsular formation. (6) vascular invasion. (7) liver capsule invasion, (8) tumor involvement at the resection margin, (9) lymph node metastasis. (10) hepatitis B. (J I) cirrhosis, and (12) fibrolamellar variant. The diagnosis of tumor recurrence was made using various radiologic imaging techniques. persistent elevation of serum ai-pha-fetoprotem, exploratory surgery. or autopsy. The median follow-up penod was 30 months, with a range of 12 to 124 months. Data are shown as mean :!: SE. For pallent survival and disease-free penod. data analysis was pert'ormed by the method of Kaplan-Meier. A P value of less than 0.05 was considered to be significant. RESULTS The mean age of the 106 patients was 43.4 ± 1.8 years (range: 2 to 70 years). There were 71 males and 35 females. Sixty-five patients (61.3%) eventually died during the fol-low-up period, 17 within 3 months of OLTx. The timing and cause of the deaths are summarized in Table 1. While noncancerous complications were responsible for all deaths within 3 months of OLTx except for that of 1 patient. tumor recurrence was considered to be a direct cause of death in 36 of the 48 patients who survived more than 3 months after OLTx. In patients who died of causes other than their tumors, 4 were found to have recurrence of their tumor, which did not directly contribute to their death. In addition. 5 patients were alive with tumor recurrence at the time of last follow-up. Therefore. tumors recurred in Table 1. TIming and C8uu of o.th In 65 Patients Who Died After Ol Tx for HCC I ntraoperatlVe death Liver failure due to technical reason Liver failure other than technICal reason SystemiC sepsis Lymphoproliferative disorders Recurrent hepatrtlS Rejecbon Myocardial infarction AIDS Cancer Total 'Inctuding 1 patient With COInadent recurrent cancer. tlncluding 2 patients WIth COII1Cldent recurrent cancer. <3mo 2 3 5 6" 17 ;o3mo 2 6t 1 l' 1 36 48 a total of 45 patients or 51 % of the patients who survived more than 3 months. Eighty-five percent of the recur-rences occurred within 12 months of OLTx. The survival rates of the 106 patients with HCC were 65%, 39%, and 38% at 1, 3, and 5 years. respectively. after OLTx. On the other hand, the survival rates of 1.622 patients who underwent OLTx for nonmalignant liver diseases were 73%. 69%. and 67% at 1. 3, and 5 years, respectively, after OLTx. The survival rates of the former were significantly lower than those of the latter (p < .001) (fig I). The tumors of II of 106 patients (10.4%) had fibrola-meHar variant HCC CFL-HCC). The overall disease-free period of patients with FL·HCC was similar to that of patients with non-FL-HCC. However, in the patients with tumors of 5 cm or greater, the disease-free period of patients with FL-HCC was significantly longer than that of patients with non-FL-HCC (P < .05) (Fig 2). The influence of each factor on the incidence of tumor recurrence in 9 patients with FL-HCC who survived 3 months is examined in Table 2. From the Department of Surgery. University of Pittsburgh. School of Medicine. Pittsburgh. PennsylVania, Address repnnt requests to ShunzabUro Iwatsuki. MD. Depart-ment of Surgery. University of Pittsburgh. 3601 Fifth Avenue. Pittsburgh, PA 15213. © 1991 by Appleton & Lange 0041-13451911$3.001 + 0 2194 Transplantation Proceedings, Vol 23. No 4 (August), 1991: pp 2194-2196 LIVER Tx FOR HEPATOCEllULAR CANCER ~D:l ~ p<o ... I ~ ····~:----.... ________ ~n~1~SOO~ .. ! ::~KKKKKKD .,,08 '\ ~ I ...... - ....... +-_ ........ . ::l en 20 i-I o[~o----~----~----~--------~ YEAR ~ HCC - ...• -Fig 1. Patient sUMVal rates after OlTx for HCC (n = 106) and for nonmahgnancy (n = 1.622) (P < .05). The influence of the above mentioned 12 clinicopatho-logic factors on the disease·free period was studied in the patients with non-FL·HCC (Table 3. univariate analysis/. Sixteen patients with non-FL·HCC who died without recurrence within 3 months postoperatively were ex· cluded. leaving 80 patients for the analysis. The favorable factors for disease·free period were tumor size of less than 5 cm in diameter. single tumor. no vascular invasion. no lymph node metastasis. presence of pseudocapsule. cir· cumscribed tumor. absence of margin invasion. and unilo-bar involvement. Among all of the factors. absence of vascular invasion was associated with the lowest rate of recurrence iP < .0001), Multivariate analysis of these factors revealed that tu· mors with gross vascular invasion were associated with an incidence of recurrence 42 times higher than that of tumors without such invasion. Other factors that independently affected tumor recurrence in order of decreasing frequency Ill~------~-----------------------------P<O.05 .... ..•..... n .. 46 ..• -_ .......... -.-......... __ ...... - ........ _ ..... I ll~----------------------------~----~ FL-HCC a 5 em NOH FI.-HCC a 5 em ___ 4_ .... _ Fig 2. Disease-free survival rates for patients with FL·HCC (n = 9) and patients With non·FL·HCC (n = 46) who sUMVed more than 3 months after receiving their transplant. Tumors less than 5 em in diameter were excluded (P < .05). 2195 Table 2. Incldenc:e of Recunence Within 3 Yea ... After Uver Tx In 8 Patients with FL-HCC (3-Month Survivors) No. Patients Tumor Character No.' w,th Recurrence Tumor sIZe <5cm 1 0 2:Scm 8 4 Tumor number Single 2 a Multiple 7 4 Vascular invaslOl1 (-) 3 0 Microsalpic 1 1 MacroscoPIC 5 3 Pseudocapsule (-) 8 3 (+) 0 0 Lymph node (-) 7 3 (+) 2 Tumor shape Circumscnbed 6 2 Infiltrative 2 Capsular invasion (-) 8 4 (+) 0 Margin (-) 9 4 (+) 0 0 Hepatitis B (-) 9 4 (+) 0 0 CirrhosiS (-) 8 4 (+) 0 Involvement ot lobes Unilobe 1 0 Bilobe B 4 ·Data not available for some pattents. were microvascular invasion. non·FL·HCC. bilobar distri· bution. and absence of pseudocapsular formation (Table 4). When the tumors were classified by their TNM stage. the survival rates of patients with tumors in stages I (n = 3) and II (n = 19) were significantly better than those of patients with tumors in stages III (n = 23) and IV (n = 50) (Fig 3). DISCUSSION Tumor recurrence is a major cause of patient death after OLTx for HCC. In the present study. the rate of recur· rence was found to be well correlated with certain distinc· tive pathologic features. In this analysis. the most statistically sigmficam adverse prognostic factor was macroscopic vascular invasion by tumor. Other adverse prognostic factors of significance included tumor size 5 cm in diameter or greater. multifo-cality of the tumor. infiltrating type (in contrast to nodular. III I I 1 I , I 2196 Tible 3. Cllnlc:opd1ologlc Fac:tora Ina 01 ..... FnIe Period In Pllllenta with Non-fL·HCC (3-Month SurvivorS) a~f%F FacIDr No. 1 y 3y Sy PValue Tumor sIZe <Scm 34 75.4 71.4 71.4 p< .001 1 ~Rcm 46 41.3 29.1 29.1 I Tumor number ., I, Single 23 82.6 78.0 78.0 p< .005 ~ ~ , Mu. 57 46.0 33.3 33.3 i Vascular invasion 1 (-) 22 95.2 95.2 95.2 p< .0001 Microscopic 30 70.0 49.8 49.8 MacroscopIC 28 11.9 0.0 PS!M Idocapsule I (-) 63 51.1 37.0 37.0 P< .01 (+) 17 81.6 81.6 81.6 Lymph node (-) 76 59.8 49.2 49.2 P= .09 jl (+) 4 0.0 \.! Tumor shape Circumscnbed 55" 70.0 63.2 63.2 P<001 .: Infiltrative 24 25.1 0.0 .' Capsular invasion , '1: H 72 57.5 47.2 47.2 P= .1 I j, (+) 8 43.8 43.8 43.8 i. Margin !. :1 (-) 74 74.3 55.9 52.2 P< .05 (+) 6 33.3 0.0 Hepatitis B (-) 60 60.6 50.4 50.4 P= .3 (+) 20 42.7 36.6 36.6 Cirrhosis (-) 59 59.3 52.2 52.2 P= .2 (+) 21 48.0 33.6 33.6 InYOivement of lobes Unilobe 44 81.6 67.6 67.6 P< .0001 Bilobe 36 28.5 28.5 28.5 • Data not 8V8I1ab1e for' patient. circumscribed type) of tumor. and bilobar involvement. Although the frequency of lymph node involvement by tumor or positive resection margin is relatively small (less than 5%). patients with these adverse factors were invari· ably found to have early tumor recurrence. qKbfe~K R......,. RIIIk of Tumor Recurrence by Mulllvlrta Analystl Factor ReIaIMt RiSk Gross vascular InvasIOn 42 Microscopic vasaJlar ilWlSion 18 Non-FL·HCC 16 Bilobar distributiOn 6 Pseudocapsular formation 4 YOKOYAMA, SHEAHAN. CARR ET AL t \ ........... ~ P<0.01 n=22 lMMr~ ..... . 80 ~ .... •••••• .. l l "....... ....... .....-------.----. I!:! 10 ........ • ••••• ~ . l '. "it... ••• .. .;c ............ _____ ...... _~-OP ~ «I ...... • ....... .. II: , ........ n-60 ~ ......... 20 TNM.. TNM. TNM PI _ •••• --.-6--Fig 3. Companson of patient sUrvIVal rates among TNM stage I and II (n = 22). III (n = 23), and IV (n = 50) tumors for patients with non-FL-HCC. The differences were significant among the groups (P< .01). Factors that were significantly associated with a better prognosis included tumor size less than 5 cm in diameter and pseudocapsular formation. Fibrolamellar variant was also a favorable factor that independently affected the prognosis. This subtype tumor of HCC. which often pres-ents in transplant candidates when the disease is at an advanced stage. is characterized by its less invasive and slow·growing nature. ~ Survival of patients with non-FL-HCC was inversely related to TNM stage. The survival of patients with stage I and II tumors far exceeded that of other groups (stages III and IV). A similar observation was reported by the Hanover group. J There were no long-term survivors seen in patients with stage IV tumors. For this poor prognostic group. adjuvant anticancer therapy may prolong the tu-mor·free survival rate. Recently. we started to investigate systemically the value of adjuvant therapy before and after transplantation for patients with hepatic malignancy. REFERENCES 1. Iwatsuki S. Gordon RD. Shaw BW. et al: Ann Surg 202:401. 1985 2. O'Grady JG. Polson RJ. Rolles K. et at: Ann Surg 207:373. 1988 3. Ringe B. Wittenkind C. Bechstein WOo BunzendahJ H. Pichlmayr: Ann Surg 209:88. 1989 4. Yokoyama 1. Todo S. lwatsulti S. Starzl TE: HepalogasU'O-enlerology 37: 155. 1989 5. StarzI TE.lwalsuki S. Shaw BW. et at: Surg Gynecol Obslel 162:145. 1986 

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Clinicopathologic factors affecting patient survival and tumor recurrence after orthotopic liver transplantation for hepatocellular carcinoma

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