Background: Hepatic epithelioid hemangioendothelioma (PHEHE) is a multifocal, low-grade malignant neoplasia characterized by its epithelial-like appearance and vascular endothelial histogenesis. The outcome of 16 patients treated with orthotopic liver transplantation (OLT) is the subject of this report. Methods: A retrospective study of 16 patients with HEHE (7 men, 9 women) with ages ranging from 24 to 58 years (mean 37 ± 10.6 years). Follow-up intervals ranged from 1 to 15 years (median of 4.5 years). Results: Actual patient survival at 1, 3, and 5 years was 100, 87.5, and 71.3%, respectively. Disease-free survival at 1, 3, and 5 years was 81.3, 68.8, and 60.2%, respectively. The 90-day operative mortality was 0. Involvement of the hilar lymph nodes or vascular invasion did not affect survival. The 5-year survival of HEHE compares favorably with that of hepatocellular carcinoma at the same stage (stage 4A): 71.3 versus 9.8% (p=0.001) Conclusions: The long-term survival obtained in this series justifies OLT for these tumors even in the presence of limited extrahepatic disease. © 1995 The Society of Surgical Oncology, Inc

American Joint Committee on Cancer

B Koneru

D. D. Karavias

H. R. Doyle

I. R. Marino

J. J. Fung

J. R. Madariaga

JG O'Grady

JY Scoazec

KG Ishak

M. A. Nalesnik

MB Kelleher

MP Holley

PJ Dean

RD Gordon

S Iwatsuki

S. Iwatsuki

SW Weiss

T Tereda

T. E. Starzl

TE Starzl

English

Madariaga, JR

Marino, IR

Karavias, DD

Nalesnik, MA

Doyle, HR

Iwatsuki, S

Fung, JJ

Starzl, TE

Name not available

Long-term results after liver transplantation for primary hepatic epithelioid hemangioendothelioma

D-Scholarship@Pitt

------LONG TERM RESULTS FOLLOWING LIVER TRANSPLANTATION FOR PRIMARY HEPATIC EPITHELIOID HEMAN(;IOENDOTHELIOMA J. R. MADARIAGA, M.D. I. R. MARINO, M.D. D. D. KARAVIAS, M.D. M.A. NALESNIK, M.n* II. R. DOYLE, M.D. S. IWATSLJKI. M.D., PH.D. T. E. STARZL. I\I.D. PH.D. Running Litle: Li\er transplantation fur epithelioid hemangim:ndothcliol11a. From the Departments of Surgery and Pathology', University or Pittsburgh School or Medicine. Correspondence: Juan R. Madariaga, M.D .. Pittsburgh Transplant Institute. 5-C Falk Clinic. 3()()I Fifth .-\q:nue. Pittsburgh. PA 1<;213 Tclcphol1L' (412) EF4~-POEF[FK Tclcrax(412) EF4~-P1~4K INTRODUCTION Epithelioid hemangioendothelioma (EHE) is a low-grade malignant neoplasm derived from endothelial cells. It was first recognized in soft tissues (l), with later reports showing that the liver may also serve as a primary site (2). We have treated 17 cases of primary hepatic EHE with orthotopic liver transplantation (OLT), and they are the subject of this report. CASE MATERIALS AND :METHODS A) Patient profile: Between November 1976 and February 19<)3, 17 patients with the diagnosis of EHE were treated with OLT either at the University Health Sciences Center of Culorado (I 971-19S0) or at the University of Pittsburgh Medical Center (1981-1993). There were ~ males and l) rem ales, with t heir ages ranging from O~ to 58 years (mean of 36 years). Follow-up intervals ranged from I to 15 years (median of 4.7 years). B) Clinical Features: The most common prcsenlatiun was abdominal pdin and hepatomegaly. ies~ comlllon signs and symptoms included weight loss, jaundice, fatigue, anorexia, ~lKIeitesI shoulder pain, splenomegaly, and d\'spm;a (Table I). In five patients the tumor was found incidentally: in [wo patients during follow-up for previously treated cancer (squamous cell carcinoma of the nasopharynx and melanoma \If the hack). in one patient during evaluation of a back injury. in one patient during a laparotomy for endometriosis, and, finally, one patient discovered mUltiple lesions in her liver while pnforming an ultrasound examination on herself. Four of the nine women h;ld taken oral contraceptives for indeterminate periods. No patient in this series had a history of l:xposure to hcpatotoxins. C) Diagnosis: In fourteen patients the diagnosis was conlirmed prior to transpLintatioll: in ~cyDen bv perclltaneous liver hiopsy and in seven by open liver hiopsy. In the remaining three gl~ltients the diagnosis was ohtained at the ---~D--"------"""-"" time of the transplant. Five patients had been originally misdiagnosed. In three cases, I to 5 years prior to transplant, the liver hiopsies were interpreted as hemangiomas (and one of these patients had a separate biopsy interpreted as a sarcoma). One patient was thought to have a hemangioma, a diagnosis he carried for 15 years without biopsy support, and only when the development of liver failure necessitated transplantation was the real nature of these lesions established. The last patient had a non-diagnostic percutaneous biopsy. The extent of tumor was staged according to the TNM classification ( 3,4). Fifteen patients were stage IV-A and two were stage IV-B. D) Treatment: All patients underwent a standard orthotopic liver transplantation (5). The first patient in our series also had a concomitant excision of a pulmonary nodule. Five patients received chemotherapy with Adriamycin-based regimens: one preoperative, three postoperative, and in one case before and after the transplant. An additional three patients had radiotherapy, two preoperatively amI one after surgt:ry. Baseline immunosuppression was accomplished with azathioprine and prednisone in one patient, cyciosporine and prednisone in 11 patients and FK50(i in the remaining 5 patients. E) Statistical Analysis: Kaplan-Meir curves were used for survival an;dysis. Ditlcrences between groups were tested for signiiieance using Breslow's test. with the significance level set at (J.().'). RESULTS Actuarial patient surviv;d at L .3. and:; year was IO()';. S(,<-;. and IlY;. respectivelv. Nine oi' 17 patients C,:;':;) arc alive and free of tumor: 7 lli' the~e patients have had Idiow·up intenais greater than.') years (median of 7.5 years). One patient died of chronic rejection. withlllll tumor. 10 months alter OL T. Diffuse metastatic disease was responsible for death in liv~ patients. Two pati~nts arc ali\'e with metastases: on~ with lung metastases three years after surgery, and the other with tumor in the liver four years after her transplant. This last patient was re-transplanted but, unfortunately, there was residual tumor at the margins of the resection. Disease-free survival at 1, 3, and 5 years was b8%, Sh~D~I and 59'/r). respectively (Fig. I). The most common sites of recurrence were the liver, lung, and bone. Involvement of the hilar lymph nodes or vascular invasion were frequent features, being present in nine patients (52%). Yet half of those patients arc currenLiy alive and frce of disease. There was no difference in the recurrence rates among patients with positive or negative nodes (Fig. 2). Likewise, vascular invasion did not affect the recurrence rate (Fig. 3). There were six postoperative complications that occurred in live patients. One patient bled lrom the Roux-en-Y loop requiring exploration on the fourth post-operative day. Eight months later he developed a biliary stricture that required percutaneous dilatation. Two patients needed a second graft because 01 primary nonfunction, at two and four days post-transplant. One patient required thrombectomy on the fourth post-operative day due to hepatic artery thrombosis. Finallv, one patient that received a second graft (for liver recurrence, [our years after the primary transplant), developed a biliary leak and intra-abdominal abscess, 10 and 14 days after her re-transplant. She was evenlllally discharged, following a prolonged hospital course. All patients recovered from their complications. DISCUSSION Epithelioid hemangioendllthelioma is a soft tisslH.! mali\lnant tumor that is characterized by its epithelial-like :lppearance and vascular endothelial histogencsis. It \\as histologic;dly identilied by Weiss and Enzinger in 1()s2 (1), and in 19~4 Ishak et aI., tirst reported a series of 32 primary EHE of the liver (2). In 1<F~UI we reported the lirst serics ()f patients (10 cases) (()) with llnresectabk EHE that were treated with liver transplantation. This report updates that initi:t\ series, :lIld adds an additional scven cases that wc havc treated since. Lin:r transplantation for hepatic malignancv remains .\urrollnded by cllIltrmcrsv, stemming frlll11 the fact that hepatocellular carcinomas and cho/ang,iocarcinomas an: :lssociated with a high recurrence r:lte :lfter liver transplantation (7,8). The clinical presentation of EHE is usually non-s[lecific. The trut: incidt:nce of this tumor is not yet known, and it is possible that many of these tumors have been misdiagnosed. especially before Ishak's rt:port in 1984 (9). The only risk factors known in these patit:nts wert: the usc of oral contraceptives (10). The final diagnosis of this neoplasm requires interpretation supplemented by immunohistochemical staining (2). Often, a wedge biopsy of the tumor is necessary to recognize the architectural features such as the intravascular or intrasinusoidal growth pattern characteristic of tht: neoplasm (2, 11). Bt:cause of the variable cellularity within any given tumor nodule, needk biopsy may be non-diagnostic if only a fibrous tissue area is sampled. Relying on only the cytologic appearance may rt:sult in overgrading the lesion as a highly malignant angiosarcoma, rather than a low grade malignancy. This, obviously, could result in limiting the treatment plan to conservative medical management, excluding the possibility of a liver transplant. In point of fact, 5 of 17 patients in the current series had an initial incorrect diagnosis. A direct comparison between the report of Ishak t:t al.,(2), of 32 patients with EH E, and thl: current series of 17 patients treated with livt:r transplantation, is not possibk. Howcver, it is interesting to note that only ninl: of 32 (281;'0 of the Ishak l:l aI., patients survi\\:d mOlT than live years. The actuarial survival rate of the EHE patients treated with livt:r transplantation in the current seril:s (117';;, at :) years) is satisfactory, and compares favorably with that sel:n in patil:nts transplanted for nonmalignant disl:ase (12). Obviously, it remains dil'licuit to propOSl: a single standard therapeutic approach for thl:Sl: tUl1lors because of their rarity and unpredictable natural histnry. Long-term survival without any specilic therapy has bl:en reported by Ishak el al. in primary hepatic EHE (nine of thl:ir 30 patients survived more than livl: Yl:ars) (2). According to Weiss and Enzinger (1) the histologic features of EH E do not predict tumor hehavior, and consl:quently it is not possible to USl: thl: histologic ch;lf<lcteristic of a giwn liver EHE as a t,(uide for therapeutic dl:cisions. Hepatic EHE is usually l1lultifm:al (1.2.11) and. therclorl:. not suitabk fl1r partial hl:patectomy (6,13.1-+). Thus. total hepatectomy and OLT is the surt,(icaltherapl:utie procedure of choicl:. The long-term survival ;lI1d di:--easc-Ircc suni\'al alter li\'Cr tranSpbl1t;ltilln ("epurted ill this paper puts EHE into a unique cilegory of primary li\er tumors. E\en fll\lowing the de\elllpmCnl 01 melastases lhrt:l: patienls survived for more than two years. It is also interesting that even in the presence of vascular invasion and positive hilar lymph nodes at transplant (findings that usually condemn to a rapid death from recurrence in all the other primary liver tumors), nine patients arc alive and free of disease. Seven paticnts recurred, and live of them died as a result of it. The survival \vas similar in patients with positive and negative nodes. We do not have sufficient data to define a role for chemotherapy, radiotherapy, or both in the treatment of this neoplasm. Thus, prospective studies will be required in this area. Also, it is not known whether lymph node dissection in conjunction with the liver transplant would affect survival. In this series. however, lymph node dissection was not systematically performed. In conclusion. liver transplantation appears to be a wrv reasonable therapeutic approach for hepatic EHE when the tumor is not resectable (other than with a total hepatectomy). The long-Ierm survival obtained in this series justifies liver transplantation for these tumors even in the presence of limited extra-hepatic disease. TABLE 1: CLINICAL PRESENTATION SYMPTOMS AND SIGNS # OF CASES l\IEAN DURATION (IN MONTHS) ABDOMINAL PAIN 'i 12.S WEIGHT LOSS 3 10 FATIGUE 1 2 ANOREXIA 1 () JAUNDICE 2 (i.S ASCITES 1 12 SHOULDER PAIN 1 1 SPLENOMEGALY 1 24 DYSPNEA 1 2 CHOLANGITIS 1 1 HEPATOMEGALY 4 7 INCIDENTAL .'\ S 1. REFERENCES Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma. Cancer 1982;50:970-981. Ishak KG, Sesterhen lA, Goodman MZD, Rabin L, Stroll1cyer FW. Epithelioid hemangioendothelioma or the liver: a clinicopathologic and rollow-up study or 32 cases. Hum Pathol 1 ')84; 15:839-852. 3. American Joint Committee on Cancer. Manual for staging of cancer. 3rd Edition. Philadelphia: JB Lippincoll, 1987, pp 87-92. -I. Hermanek P, Sobin LH, cds. TNM classification or malignant tumors. Fourth Edition. Berlin: Springer- Verlag, 1987.pp 53-55. 5. Starzl TE, Iwatsuki S. Esquivel CO, et al. Refinements in the surgical technique or liver transplantation. Semin Liver Dis ll)85;5:3-19-35(). (). l\larin() IR, Todo S. Tzakis AC;, Klintmall11 (;, Kelleher M. Iwatsuki S. Starzl TE. d al. Treatment of hepatic hemangiocndothelioma with li\cr transplantation. C:lnccr l')88;207()-2ll8-1. 7. Koneru B. Cassavilla A. Bowman .I, lwatsuki S. Starz.l TE. Livcr transplantation fur malignant tumors. Gastroenerol Clin North Am I')88: 17: 177-<)3. 8. Iwatsuki S, Starzl TE, Sheahan DG, Yokll\"ama I. Dcmetris A.I, Toelo S, Tzakis A(; et al. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 19l )[ :21-1:221-229. 'i. Weiss SW, Ishak K(;. Dail DH. Enzinger Ft\1. Epithelioid hcmangioendothelioma - a vascular tumor orten mistaken for a carcinoma. Cancer I ()82:S1):'nO-SI. Ill. Dean PJ, Haggiu C. O'Hara C.I. t'-.lalie,nant cpitheliohem:lne,iocndothcliom:1 or thc livcr in young \\\)l11cn. Rciatiunship to llral cuntraccpti\c thC. Am.l Sure, P:lthul \')8S:<>'iS-70-l. REFERENCES CON'T: 11. Kelleher MB, Iwalsuki S, Sheahan DG. Epithelioid hemangioendothelioma or liver. Am J Surg Palhol 1989;13:999-10118. 12. Gordon RD, Fung J, Tzakis ACi, Todo S. Stieber A, Bronslher 0, Martin 1\1 et al. Liver transplantation al the Uni\'ersity or Pittsburgh 1984-1990. In: Clinical Transplants 1991. Los Angeles, CA,: UCLA Tissue Typing Laboratory, 1991:105-11K. 13. Scoazec .IY, Lamy P, Degott C, Reynes M, Feldmann C;, Bismuth H, Benhamon C;P. Epithelioid hemangioendothelioma of the liver. Diagnostic l'catures and role of liver transplantation. Gastroenterology 19,s,s;94: 1447-1453. j·t O'Grady JG, Polson R.I, Rollo SK. Caine RY, Williams R, Liver transplantation f()r malignant disease. Results in 93 consecutive patients. Ann Surg 1988;207:373-9. 100-1(17) O-r--i -80 -t '-" 1 1(8) l (1 ) (7) '-" ~ .-. 60 ~ 0 "'-"" -C'CS -0-Patient survival (n=17) > 4M~ .- ~ -0-Disease-free survival :s en 20 o~--------------------------------------------------------~ o 2 4 6 8 10 12 14 Years After Transplantation c 0 ......, t) co L-'+- Q) Q) L-'+- I Q) t) c Q) L-L-::J t) Q) 0:: Vascular invasion and recurrence 1.0, f~ --------l .8 .6 ----.4 .2 0.0 i +-I I ---,-----024 6 8 10 12 14 16 Time Post Transplant Vascular Invasion o Invasion ::: No Invasion p=0.8 (Breslow) Lymph node status and recurrence " 1.0,. I ~ 1,-I .8 LC c ---l 0 I ~ (,) -l ro '-.6 4- Q) Q) '-4- I Q) (,) c Q) .4 '- ~ ::J (,) Q) n::: .2, Lymph Node Status 0 Positive -L I 0 Negative 0.0 ~ ___ p=0.9 (Breslow) I I --r~~ I I I 1 0 2 4 6 8 10 12 14 16 ...... Time Post Transplant 

/~nna/s of SlIrllica/ Onc%",. 2(61:483-187 . Published by Lippincott-Raven Publishers r \ 995 The SocIety of SurgIcal Oncology. Inc. Long-term Results After Liver Transplantation for Primary -'- Hepatic Epithelioid Hemangioendothelioma J. R. Madariaga. MD, 1. R. Marino, MD, D. D. Karavias, MD. M. A. Nalesnik, MD, H. R. Doyle, MD, S. Iwatsuki, MD. PhD, J. J. Fung. MD, PhD, and T. E. StarzI, MD, PhD Background: Hepatic epithelioid hemangioendothelioma (PHEHEl is a multifocal. low-grade malignant neoplasia characterized by its epithelial-like appearance and vascular en-dothelial histogenesis. The outcome of 16 patients treated with orthotopic liver transplan-tation (OL T) is the subject of this report. Methods: A retrospective study of 16 patients with HEHE (7 men. 9 women) with ages ranging from 24 to 58 years (mean 37 :!: 10.6 years). Follow-up intervals ranged from I to 15 years (median of 4.5 \ ears). Results: Actual patieni survival at 1. 3. and 5 years was 100. 87.5. and 7\.3%, respec-tively. Disease-free survival at 1,3. and 5 years was 81.3. 68.8, and 60.2%. respectively. The 90-day operative mortality was O. Involvement of the hilar lymph nodes or vascular invasion did not affect survival. The 5-year survival of HEHE compares favorably with that of hepatocellular carcinoma at the same stage (stage 4A): 71.3 versus 9.8% (p = 0.001) Conclusions: The long-term survival obtained in this series justifies OL T for these tumors even in the presence of limited extrahepatic disease. Key Words: Liver transplantation-Epithelioid hemangioendothelioma. Epithelioid hemangioendothelioma (EHE) is a low-grade malignant neoplasm derived from endo-thelial cells. It was first recognized in soft tissues (1). with later reports showing that the liver may also serve as a primary site (2). We have treated 16 cases of primary hepatic EHE with orthotopic liver transplantation (OLTl. and they are the subject of this report. MATERL-\LS AND METHODS Patient profile Between November 1976 and February 1993. 16 patients with the diagnosis of EHE were treated Received April 4. 1994: accepted September :::. 1994. From the Departments of Surgery igKoK~fKK I.R.M .. D.D.K .. H.R.D .. S.I.. J.J.F .. T.E.S.I and Patholog, E~fKAKkKlK Univer-,ny of Pittsburgh School of ~fedicineK Pittsburgh. Pennsylvanaa. lSA. Address correspondence and reprint requests to Dr. J. R. ~ladariagaK Pillsburgh Transplant Institute. 4th Floor Falk Clinic. 3601 Fifth Avenue. Piltsburgh. PA 1:':13. L:SA. ~Ug with OLT either at the University Health Sciences Center of Colorado ( 197Cr-1980) or at the University of Pittsburgh Medical Center (1981-1993). There were seven men and nine women. with ages ranging from 24 to 58 years (mean of 37 ;:!: 10.6 years). Fol-low-up intervals ranged from I to 15 years (median of 4.5 years 1. Clinical features The frequency of symptoms is depicted in Table I. In five patients the tumor was found incidentally: in two patients during follow-up for previously treated cancer (squamous cell carcinoma of the na-sopharynx and melanoma of the back), in one pa-tient during evaluation of a back injury, in one pa-tient during a laparotomy for endometriosis. and. finally. one patient discovered multiple lesions in her liver while performing an ultrasound examina-tion on herself. Four of the nine women had taken oral contraceptives for indeterminate periods. No patient in this series had a history of exposure to hepatotoxins. 484 1. R. MADARIAGA ET AL. TABLE l. Clinical prese'lrQrion Frequency Mean duration Symptoms and signs (%1 (mos) Abdominal pain 56.2 12.5 Weight loss 18.7 10 Fatigue 6.5 2 Anorexia 6.25 6 Jaundice 12.5 9.5 Ascites 6.25 12 Shoulder pain 6.25 I Splenomegaly 6.25 24 Dyspnea 6.25 2 Cholangitis 6.25 I Hepatomegaly 25 7 Incidental 3l.25 8 Diagnosis In 14 patients the diagnosis was confirmed before transplantation: in seven by perc!ltaneous liver bi-opsy and in seven by open liver biopsy. In the re-maining two patients the diagnosis was obtained at the time of the transplant. Four patients had been misdiagnosed originally. In three cases. 1-5 years before transplant, the liver biopsies were interpreted as hemangiomas (and one of these patients had a separate biopsy interpreted as a sarcoma). One patient had a nondiagnostic per-cutaneous biopsy. In one case the native liver also had unsuspected cirrhosis (the only case of cirrho-sis associated with EHE in this series). The extent of the tumor was staged according to the pTNM classification (3.4). Fourteen patients were stage IY-A and two were stage IY-B. Treatment All patients underwent a standard orthotopic liver transplantation (S). The first patient in our se-ries also had a concomitant excision of a pulmonary nodule. Five patients received chemotherapy with Adriamycin-based regimens: one preoperative. three postoperative. and in one case before and af-ter the transplant. An additional :hree patients had radiotherapy. two preoperativel\' ::md one after sur-gery. Baseline immunosuppression was accom-plished with azathioprine and prednisone in one pa-tient. with cyclosporine and prednisone in 10 pa-tients and with FKS06 and prednisone in the remaining five patients. Statistical analysis Survival analysis was performed using the method of Kaplan-Meier. Differences between groups were tested for significance using Breslow's test. with the significance level set at O.OS. .-\nn pur~ Oneol. Vol. 1. No.6. 1995 RESULTS Actuarial patient survival at I. 3. and S years was 100,85.7, and 71.3%. respectively (Fig. I). Nine of 16 patients (6S9C) are alive and free of tumor; seven of these patients have had follow-up intervals >5 years (median of7.5 years). Diffuse metastatic dis-ease was responsible for death in five patients from 16 months to 180 months after OL T (median: 43 months). Two patients are alive with metastases: one with lung metastases 3 years after surgery, and the other with tumor in the liver ~ years after her transplant. This last patient was retransplanted but. unfortunately. there was residual tumor at the mar-gins of the resection. Disease-free survival at 1. 3. and 5 years was 81.3, 68.8. and 60.2%. respectively (Fig. 1). In-volvement of the hilar lymph nodes or vascular in-vasion was a frequent feature. being present in nine patients (S6.25'CL 01evertheless. half of those pa-tients are currently alive and free of disease. There was no difference in the recurrence rates among patients with positive or negative nodes (Fig. 2). Likewise, vascular invasion did not affect the re-currence rate (Fig. 3). The most common sites of recurrence were the liver. lung, and bone (Table 2). There were six postoperative complications that occurred in five patients. One patient bled from the Roux-en-Y loop. requiring exploration on the 4th postoperative day. Eight months later he developed a biliary stricture that required percutaneous dila-tation. Two patients needed a second graft because of. primary nonfunction. at 2 and ~ days after trans-plant, respectively. One patient required throm-bectomy on the ~th postoperative day due to he-patic artery thrombosis. Finally. one patient re-ceived a second graft (for liver recurrence, 4 years ~ '" :: > ~ ( 161 !OO • I , ~ 80 J i 60 I .... I .10 ~ I '1 20 1 ~ I J I 0 II-- 1.. ,Ql ., - -:--------, ........ ., - ..L ,8) ·-------------~q 2 • = :lJ1.en: SU'J'vdl (n.1S) • J'se3Se-'re:! 5'.J(vlval Years alter qranp~la~:atlon FIG.!. Actuarial and disease· free survival. 5 r I LIVER TRANSPL4..YT FOR PHEHE 485 100 • I I 80 J ... II ~ . , :J I C l :J SM~ :l ~ OJ 40 o POSItive U • NegallY. " 2: l p-09 (BreSlOW, a 2 -4 5· Years Post qranscIa-~atlon FIG. 2. Hilar lymph node status and recur.ence after transplan-tation. after the primary transplant). and developed a bili-ary leak and intraabdominal abscess. 10 and 14 days after her retransplant. respectively. She was finally discharged. after a prolonged hospital course. All patients recovered from their complications. DISCUSSION EHE is a soft-tissue malignant tumor that is char-acterized by its epithelial-like appearance and vas-cular endothelial histogenesis. It was histologically identified by Weiss and Enzinger in 1982 (1). and in 1984 Ishak et al. first reported a series of 32 primary EHE of the liver (2). In 1988. we reported the first series of patients (10 cases) (6) with unresectable hepatic epithelioid hemangioendothelioma (HEHE) that were treated with liver transplantation. This lOa .. I I 80 --n , " " • :; 60 a> g 1,_ ~ 40 '3 .::: invaSion u • ~~o Invasion :l ;:: 20 ;l.0 8 I Bres-: ,', a 0 2 .; 5 '(ears Post Trars: ::-:a!lon FIG. 3. Vascular invasion and recurrerKc~ ~iter transplantation. report updates that initial series. and adds an addi-tional six cases that we have treated since. Liver transplantation for hepati.: malignancy re-mains surrounded by controversy. stemming from the fact that hepatocellular carcinomas and cholan-giocarcinomas are associated with a high recur-rence rate after liver transplantation (7.8), The clinical presentation of HE HE is usually nonspecific. The true incidence of this tumor is not yet known, and it is possible that many of these tumors have been misdiagnosed. especially before Ishak's report in 1984 (9). The only risk factors known in these patients were the use of oral con-traceptives (10). Often, a wedge biopsy of the tumor is necessary to recognize the architectural features such as the intravascular or intrasinusoidal growth pattern characteristic of the neoplasm (2.6.11). Im-munohistological staining for Von Willebrand factor TABLE 2. Recurrence and survival Time to SUf\IVaJ Case no, Primary Age/seK~ Recurrence Site of recurrence recurrence (yrs)" tIme I yrsl" Outcome HEHE 28/F Yes Liver 1.1 15 DWT HEHE 50/M Yes Liva lung UII.5 ~I .: DWT HEHE 43/M Yes Lung 0,9 AWT 4 HEHE 53/M Yes Bon~ lung 03,09 (.l DWT 5 HEHE 381M Yes iiyD~r lung 2,311"+ ~ DWT 6 HEHE 281M No :-; • .>. :-;A ~_P AWOT 7 HEHE 281M No N .. \ kI~ ,- AWOT 8 HEHE 41/F No :-; . .>. NA 6,) AWOT 9 HEHE JI/F No NA NA -AWOT 1O HEHE 46/F Yes Li\'er 4 , AWT II HEHE 25/F Yes Livalung II 13 DWT 12 HEHE 29/F No NA kK~ 6 AWOT 13 HEHE 58/M No NA :-; • .>. U AWOT 14 HE HE 33/F No NA N . .>. 10.5 AWOT 15 HEHE 24/F No kK~ NA -3 AWOT 16 HEHE 32JF No N . .>. NA - , AWOT --HEHE. hepatic epithelioid hemangioendothelioma; A WOT. alive "ithout tumor; AWT, alive with tumor; DWT, died with tumor. " From day of transplant. ,"'.nn pur~ O"eal. Vol, 1 . .vo. 6. 1995 .+86 1. R. MADAR1AGA ET AL. 100 I I PE"E 80 I L -~ 60 ' > ;; 3 '" 40 ,< I I He::: 20 L..... 0 a 2 4 5 p=O.OOOl Year alter qransolaKKKI~:n : _ ;:>nmary Epithelioid Hemangloe-:::nehoma (PEHE) I ' ___ "...:' e.:.ca::.:.to:.:c.:.el.:.lul.:.ar;..C:.:a;..rc;..in.:.om---c-a ;..1 H_C_: _____ -'I., FIG. 4. Survival after liver transplantat:0r1 for stage IV -A he-patic hemangioendothelioma In = 14) ver;(;s hepalocellular car-CInoma (n = 10::). may also be of use in distinguishing the endothelial-derived tumor cells from adenocarcinoma (2). Be-cause of the variable cellularity within any given tumor nodule. needle biopsy may be nondiagnostic if only a fibrous tissue area is sampled. Relying on only the cytologic appearance may result in over-grading the lesion as a highly malignant angiosarco-ma. rather than a low-grade malignancy. This. ob-viously _ could result in limiting the treatment plan to conservative medical management. excluding the possibility of a liver transplant. In point of fact. 4 of 16 patients in the current series had an initial incor-rect diagnosis. A direct comparison between the report of Ishak et al. (2) of 32 patients with HEHE and the current series of 16 patients treated with liver transplanta-tion is not possible. However. it is interesting to note that only 9 of 32 (28%) of the Ishak et a!. pa-tients without any specific therapy survived >5 years. The actuarial survival rate of the HEHE pa-tients treated with liver transplantation in the cur-rent series (/1.3% at 5 years) is quite similar to that which we see in patients transplanted for nonmalig-nant disease (12). The survival afier OLT for stage IY-A HEHE (n = f~F compares more than favor-ably with that of hepatocellular carcinoma at the same stage (unpublished data. Fig. 4). Obviously. it remains difficult to propose a single standard therapeutic approach for these tumors be-cause of their rarity and unpredic:able natural his-lOry. According to Weiss and Enzinger (I). the his-tologic features of HE HE do not predict tumor be-havior. and consequently it is not possible to use the histologic characteristic of a given liver EHE as a guide for therapeutic decisions. Hepatic EHE is usually multifocal (1.2.6,11) and. therefore. not suitable for partial hepatectomy (6.13-16). The role K~nn Surg Oneal. "tJ/. 2 .. Yo. 6. 1995 of chemotherapy without liver transplantation is un-known because only a few cases have been pub-lished in the literature (15.17); however, in our own series there was no response (data not shown). Thus. total hepatectomy and OlT is the surgical therapeutic procedure of choice. The long-term sur-vival and disease-free survival after liver transplan-tation reported in this article confirms the unique nature of this malignant tumor. Even after the de-velopment of metastases. three patients survived for> 2 years. It is also interesting that in the subset of nine patients \liith vascular in\asion and positive hilar lymph nodes at transplant I findings that usu-ally condemn to a rapid death from recurrence in all the other primary liver tumors). there were no mor-talities and all of them are free of disease. Seven patients had recurrence. and five of them died as a result. The survivals were similar in patients with positive and negative nodes. We do not have suffi-cient data to define a role for chemotherapy. radio-therapy. or both in the treatment of this neoplasm. Thus. prospective studies will be required in this area. In conclusion. liver transplantation appears to be a very reasonable therapeutic approach for hepatic EHE when the tumor is not resectable (other than with a total hepatectomy). The long-term survival obtained in this series justifies li\t:!r transplantation for these tumors. even in the presence of limited extrahepatic disease. REFERENCES L Weiss SW. Enzinger F:v1. Epithelioid hemangiol!ndothelio-rna. Cancer 1982:50:97G-3 L , Ishak KG. Seslerhen IA. Goodman \IZD. Rabin L. Stro-meyer FW. Epithelioid hemangioendothelioma of the liver: a clinicopathologic and follow-up swdv of 32 cases. Hum Pat/wi 1984: 15:839-52. 3. American Joint C0mmIltee on Cancer. .Hiln/lal jilr staging of cancer. 3rd ed. Philaddphia: JB LipPincott. 1987:87-92. 4. Hermanek P. SobIn LH. eds. T.V.\/ dass/lieulion ,,(malig-nant (lIIt/ors. 4th ed. Berlin: Sprtnger·\/erlag. 1987:53-5. 5. Starzl TE. [watsuki S. Esquivel CO. et al. Rdinements in the surgical technique of liver transC'lantalion. Semin Liver Dis 1985:5:3 .. 9-56. 6. :v1arino IR. Todo S. Tzakis AG. Klintmalm G. Kelleher M. lwatsuki S. Starzl TE. e! al. Treatment of hepatic heman-gioendothelioma with liver transpiJnt:Hion. Cancer 1988: 2079-8 ... 7. Koneru B. Cassanlla .-\. Bowman J. ly~atsukl S. Starzl TE. Liver transplantation for malignant tumors. Gustroenerol Clin Norrli Am 1988:17:177-93. 8. lwatsuki S. Starzl TE. Sheahan DG. Yokoyama I. Demetris A1. Todo S. Tzakis .-\G. et al. Hepatic resection KD:~rRus transplantatIOn for hepatocellular carCInoma . . -\lIn Surg 1991 :214:221-9. 9. Weiss SW. Ishak KG. Dail DH. Enzinger Fyi. Epithelioid LIVER TRANSPLANT FOR PHEHE 487 hemangioendothelioma-a vascular tumor often mistaken for a carcinoma. Cancer 19UO;RM:9T~1K 10. Dean Pl, Haggitt C, O'Hara CJ. Malignant epithelioheman-gioendothelioma of the liver in young women: relationship to oral contraceptive use. Am J Surg Palhol 1985;695-704. 11. Kelleher MB. Iwatsuki S. Sheahan DG. Epithelioid heman-gioendothelioma of liver. Am J Sur? Pathol 1989;13:999-1008. 12. Gordon RD, Fung l, Tzakis AG. Todo S, Stieber A, Bron-sther 0, Martin M. et al. Liver transplantation at the Uni-versity of Pittsburgh 1984-1990. In: Clinical transplants 1991. Los Angeles: UCLA Tissue Typing Laboratory. 1991: 105-88. 13. Scoazec JY, Lamy p, DegOlt C. Reynes M, Feldmann G. Bismuth H. Benhamon GP. Epithelioid hemangioendoth·eli-oma of the liver: diagnostic features and role of liver trans-plantation. Gastroenterolugy 1988:94: 1447-53. 14. O'Grady JG. Polson RJ. Rollo SK. Caine RY. Williams R. Liver transplantation for malignant disease: results in 93 consecutive patients. Ann Surg 1988:207:373-9. IS. Tereda T. Hoso M. Kono N, Watanabe K. Nakanuma Y. Epithelioid hemangioendothelioma of the liver in primary biliary cirrhosis: a case report. Acca Pachal Jpn 1989;39:607-11. 16. Dean PI. Haggitt RC. O'Hara C1. Malignant epithelioid hemangioendothelioma of the liver in young women: rela-tionship to oral contraceptive use. Am J Surg Parhol 1985; 9:695-704. 17. Holley MP. Cuschieeri A. Epithelioid hemangioendothelio-ma of the liver: objective response to hepatic intraarterial 5-FU. £ur J 511rg Oneal 1989;15:i3-8. Ann Surg Oneal. Vol. Z. No.6, /995 

Crossref

http://d-scholarship.pitt.edu/5270/1/31735062133487.pdf

Long-term results after liver transplantation for primary hepatic epithelioid hemangioendothelioma

Abstract

Similar works

Full text

Available Versions

Name not available

D-Scholarship@Pitt

D-Scholarship@Pitt

Name not available

Crossref