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Liver Transplantation for Non-hepatocellular Carcinoma Malignancy: A Single-Center Experience
Liver Transplantation for Non-hepatocellular Carcinoma Malignancy: A Single-Center Experience Alessandra Maria Mont`Alverne Pierrea,*, Camila Monteiro Verasa, Ticiana Mota Esmeraldoa, Maximilian Pinho Schwermannb, Marina Seixas Studart e Nevesa, José Eudes Bastos Pinhoa, and Ivelise Regina Canito Brasila a Liver Transplantation Division, Fortaleza General Hospital, Fortaleza, Ceara, Brazil; and bUniversidade de Fortaleza, Fortaleza, Ceara, Brazil
ABSTRACT Background. Liver transplantation has become an effective treatment for selected patients with hepatocellular carcinoma with excellent outcomes. More recent reports have described improved outcomes in liver transplantation in a subset of patients with other malignancies like hilar cholangiocarcinoma, unresectable hepatic epithelioid hemangioendothelioma and hepatic metastasis from neuroendocrine tumors. However, hepatic angiosarcoma remains an absolute contraindication to liver transplantation because of the poor outcome. Objectives. The present study aims to describe liver transplantation for nonhepatocellular carcinoma malignancy. Methods. A retrospective analysis of patients and review of the literature was performed. Results. A total of 5 patients with non-hepatocellular carcinoma malignancy on explants histopathologic findings were identified. They presented hepatic epithelioid hemangioendothelioma (1), neuroendocrine tumor (1), angiosarcoma (1) and cholangiocarcinoma (2). The mean length of follow-up was 22.8 37.67 (range, 2-90 months). Of 5 patients evaluated, 3 patients remain with stable graft function. Conclusion. Future investigations are necessary to redefine the indications of liver transplantations to treat non-hepatocellular carcinoma malignancy and its limitation.
L
IVER transplantation (LT) represents the best treatment in patients with decompensated cirrhosis, unresectable primary hepatic malignancies and acute liver failure in which spontaneous recovery is not anticipated. Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, and in a selected group of patients with cirrhosis, who fulfill the Milan criteria, liver transplantation offers the most reasonable expectation for curative treatment. These criteria, introduced by Mazzaferro in 1996, were as follows: (1) single tumor diameter less than 5 cm; (2) not more than 3 foci of tumor, each one not exceeding 3 cm; (3) no angioinvasion; and (4) no extrahepatic involvement, demonstrated a 5-year recurrence-free survival rate of 83% [1]. This favorable result could expand the LT as a therapeutic option for other malignancies of the liver such as hepatic epithelioid hemangioendothelioma (HEHE), hepatoblastoma,
ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, XX, 1e5 (2019)
unresectable liver metastases due to neuroendocrine tumors, cholangiocarcinoma (CC), sarcomas and recently colorectal metastatic lesions. The apparent limitation of expanding this treatment to a larger group of patients is the organ shortage. Therefore, the indications for LT for non-hepatocellular malignancy and its limitation will continue to be redefined through future investigations [2,3]. MATERIAL AND METHODS This study was conducted at the Liver Transplant Division of the General Hospital of Fortaleza (HGF, Fortaleza, Brazil). We
*Address correspondence to Alessandra Maria Mont’Alverne Pierre, Rua Coronel Alves Teixeira, 1578 Joaquim Távora, Fortaleza CE 60130-001, Ceara, Brazil. Tel: (085)34578085. E-mail: [email protected] 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.09.001
1
2
MONT`ALVERNE PIERRE, VERAS, ESMERALDO ET AL Table 1. Demographic and Epidemiologic Characteristics of the Population Studied (N [ 5)
No
Diagnosis of Non-HCC Malignancy before LT
Age at LT (y)
Sex
Causes of LT
1 2
33 55
Male Male
3 4 5
69 63 30
Male Male Female
Epithelioid hemangioendothelioma Unresectable liver metastases due to neuroendocrine tumor Cryptogenic cirrhosis Hepatitis C virus cirrhosis Primary sclerosing cholangitis cirrhosis
Yes Yes No No No
Explanted Liver
Epithelioid hemangioendothelioma Unresectable liver metastases due to neuroendocrine tumor Incidentally angiosarcoma Incidentally cholangiocarcinoma Incidentally cholangiocarcinoma
Abbreviation: HCC, hepatocellular carcinoma.
retrospectively analyzed the hospital records to evaluate our liver transplant receptors between December 2009 and July 2018 for the presence of non-hepatocellular malignancy by focusing on explants histopathologic findings. The following parameters were studied in all patients: age at transplantation, sex, indication for LT, primary immunosuppression, explants tumor characteristics, recurrence-free survival after LT, recurrent cancer treatment, overall survival after LT and cause of death. The diagnosis of malignancy was established by explants histopathologic findings. Initial immunosuppression was based on calcineurin inhibitors (tacrolimus), prednisone (until the third month after LT), supplemented with mycophenolate sodium or mammalian target of rapamycin inhibitor (mTOR) (everolimus) according to our actual study protocol. Modifications in doses or compounds were done individually, dependent on the clinical course.
Follow-up Our patients were examined according to our protocol, which includes liver function tests, routine blood tests and routine monitoring blood levels of tacrolimus and everolimus once a week in the first month, every 14 days from the second to the third month, every month from the fourth to the sixth month and then every 3 months. Bone scintigraphy and chest and abdominal computed tomography (CT) were performed whenever necessary and every 6 months from LT to the second year and then every year until 5 years after LT. Results were expressed as mean standard deviation. Statistical analyses were performed with SPSS software version 20 (IBM, Armonk, NY, United States).
RESULTS Patients’ Characteristics
From December 2009 to July 2018, 379 patients received an orthotopic liver transplant in our institution. A total of 5 patients with non-hepatocellular carcinoma malignancy on explants histopathologic findings were identified.
The demographic data of patients are shown in Table 1. Five patients were included, 80% men and mean age of 50 17. The indications for LT were due hepatic epithelioid hemangioendothelioma (n ¼ 1), unresectable liver metastases due to neuroendocrine tumors (n ¼ 1), cryptogenic cirrhosis (n ¼ 1), hepatitis C (n ¼ 1) and primary sclerosing cholangitis (n ¼ 1). The recipients’ explanted livers showed hepatic epithelioid hemangioendothelioma, neuroendocrine tumor, angiosarcoma, cholangiocarcinoma, and cholangiocarcinoma, respectively. Immunosuppression
All patients received triple-therapy-based immunosuppression with an initial calcineurin inhibitor (tacrolimus) in combination with prednisone (tapered within 3 months after LT) and everolimus (n ¼ 4) or mycophenolate sodium (n ¼ 1) as listed in Table 2. One patient changed mycophenolate mofetil to everolimus after cancer diagnosis in explant, and another patient was converted to mycophenolate mofetil due to dyslipidemia. Modifications in doses were done individually, and always the use of lower doses was preferred, thus reducing adverse effects associated with such drugs. No patient had an episode of biopsy-proven acute cellular rejection. Explant Tumor Characteristics
Patient 1: A 33-year-old man underwent LT due to HEFE, and a multifocal epithelioid proliferation was identified. Immunohistochemical staining positive for cytokeratin 7 and CD 31 in explant. Patient 2: A 55-year-old man had a midgut neuroendocrine tumor (ileum) and underwent surgical resection, enteroanastomosis, and lymphadenectomy. Biopsy revealed 2.7 1.6 cm neuroendocrine well-differentiated G3 tumor
Table 2. Primary and Secondary Immunosuppressive Regimens of the Population Studied (N [ 5) Immunosuppressive Regimens No
1 2 3 4 5
Primary
Secondary
Rejection
TAC, EVR, PD TAC, EVR, PD TAC,MMS, PD TAC, EVR, PD TAC, EVR, PD
Nc TAC,MMS TAC, EVR, PD Nc Nc
No No No No No
Last TAC Serum Concentration (Co)
2.6 4.3 2.3 3.6 3.2
ng/mL ng/mL ng/mL ng/mL ng/mL
Abbreviations: EVR, everolimus; MMS, mycophenolate sodium; Nc, no change; PD, prednisone; TAC, tacrolimus
Last EVR Serum Concentration (Co)
3.7 ng/mL ————— 2.5 ng/mL 2.0 ng/mL 2.0 ng/mL
NON-HEPATOCELLULAR CARCINOMA MALIGNANCY
with a Ki 67 proliferation index of 2% and no angiolymphatic invasion. Eight months later, he presented with multiple large liver metastases with no other spread to a secondary organ. The patient was submitted to transarterial chemoembolization and somatostatin analogue, but a contrast-enhanced CT showed multiple bilateral lesions in the liver, thus he underwent LT. Explant histopathological features confirmed diagnosis (NET). There were 4 nodules (the largest 13 11 cm) with cribriform tumor structure and low mitotic index. Patient 3: A 69-year-old man had decompensated cryptogenic cirrhosis leading to LT. He was classified ChildPugh C with 11 points, and his Model for End-Stage Liver Disease (MELD) score was 29. The explanted liver revealed a 1.2 cm tumor with a spindle cell pattern, high-grade nuclear atypia and immunohistochemical staining positive for CD34. Therefore, angiosarcoma was confirmed. Patient 4: A 63-year-old man underwent LT due to decompensated cirrhosis (hepatitis (C) and hepatocellular carcinoma. He was classified Child-Pugh B with 7 points, and despite a MELD score of 10, he was prioritized for HCC. The diagnosis of HCC was made before LT with CT and magnetic resonance imaging. Explant featured 3 lesions (the largest 3 2 cm) with well demarcated, firm, desmoplastic reaction, moderately differentiated adenocarcinoma G2, and no vascular invasion. Immunohistochemical staining positive for cytokeratin 7, cytokeratin 19 and negative for GATA 3. Histopathologic findings resulted in a diagnosis of cholangiocarcinoma. There was no HCC on explant. Patient 5: A 30-year-old woman had cirrhosis and underwent LT due to primary sclerosing cholangitis (PSC) with no inflammatory bowel disease, Child-Pugh B with 8 points and a MELD score of 20. Explant revealed a 2.6 1.5 cm pale tumor, with well-demarcated, firm, moderately differentiated G2 cholangiocarcinoma and no vascular invasion.
OUTCOMES
The mean length of follow-up was 22.8 37.67 (range, 2-90 mo). Of 5 patients evaluated, 3 are still alive and remain with stable graft function. The primary diagnosis of these patients was hepatic epithelioid hemangioendothelioma, cholangiocarcinoma, and neuroendocrine tumor. The follow-up was respectively 5, 7, and 90 months. No recurrence was noted. The patient who underwent LT due to hepatitis C cirrhosis and cholangiocarcinoma was found in explant developed pulmonary sepsis 2 months after LT and died. Malignancy recurrence was detected radiologically in one patient 1 month after LT. He presented recurrent angiosarcoma metastatic to the lung. The proposed course of treatment involved palliative chemotherapy. The patient was administered paclitaxel. Six months after uneventful chemotherapy, he developed chronic anemia and died 10 months after LT.
3
DISCUSSION
Liver transplantation is an effective treatment for hepatocellular carcinoma, in selected patients whose tumor masses do not exceed the Milan criteria, providing excellent longterm survival. Although, different studies, comparing outcomes from hepatectomy and LT for primary HCC, have been shown that disease-free survival is superior when LT is considered, others show different results [4,5]. Considering that the Milan criteria are limited and that a significant proportion of HCC patients are not eligible for transplantation, other criteria have been proposed. The University of California San Francisco has shown considerable results while including patients with solitary tumor with less than 6.5 cm, or 3 nodules with the largest lesion with 4.5 cm and total tumor diameter less than 8 cm [6] .The incorporation of tumor markers such as alpha fetoprotein in the inclusion criteria for HCC LT also has been proposed [7]. The decision to perform liver transplantation in a patient with non-HCC malignancy relies on the survival probabilities with LT. Vascular tumors of the liver in adult patients are a heterogeneous group with different behavior that includes cavernous hemangioma, a common benign tumor; epithelioid hemangioendothelioma, an enigmatic tumor with unpredictable malignant behavior but usually lowgrade malignant tumor and angiosarcoma, a very aggressive tumor [8,9]. Hepatic epithelioid hemangioendothelioma are bilobar tumors in almost all cases. Chemotherapy and radiation appear to offer little benefit. Resection is usually indicated, but the extensive multifocal nature of the disease can make surgical resection difficult and has made LT a more attractive option [10,11]. A retrospective study of 16 patients with HEHE showed survival 100%, 88%, and 71% at 1, 3, and 5 years, respectively. The presence of extrahepatic disease at the time of transplantation did not affect survival time [12]. In Brazil, LT is recommended to patients with unresectable HEHE and no extrahepatic spread of the tumor. They receive a MELD score of exception points and therefore have faster access to transplant. Our patient presented with multifocal HEHE and no extrahepatic disease before LT. To date, he is still alive with no recurrence and in a good clinical condition. Primary angiosarcoma is a rare malignant neoplasm and accounts for 2% of all primary tumors of the liver. In the United States the prevalence varies from .14 to 0.25 per million [13]. Thorotrast and its use in angiography, arsenic and vinyl chloride monomer in addition to androgenic anabolic steroids are frequently listed as risk [14,15]. Due to the characteristic of the aggressive tumor and the delay in diagnosis, the prognosis is very poor [16]. A retrospective study of 22 patients with angiosarcoma submitted to LT reported to the European Liver Transplant Registry, showed a median overall survival of 6 months and no patient survived for more than 2 years after LT. The use of an
4
mTOR inhibitor as an immunosuppressive treatment after LT has been suggested in many clinical cases, but this conversion does not inhibit the development of tumor metastases [17]. Compared to the above data, our present study reports a patient with incidental angiosarcoma in explant histopathologic findings and with poor prognosis. Immunosuppression was based on mTOR (everolimus). The recurrence occurred one month after LT and the patient survived for only ten months. Unacceptable survival and recurrence rates currently prohibit the use of LT in hepatic angiosarcoma. Neuroendocrine tumors are a group of tumors that originate in several locations, including the gastrointestinal tract, lung and pancreas [18]. In general, neuroendocrine tumors originating from the gastrointestinal tract are slowgrowing and are often discovered in a metastatic phase. Surgical resection for hepatic metastasis in a patient with NET, if possible, is the primary line treatment option. However, if metastases are limited to the liver, LT is a viable treatment option. Metastatic liver disease from NET is considered the only indication for LT for a metastatic cancer [2]. Thus, only patients with tumors presenting with biologically favorable features, such as limited bulk and absence of systemic disease are potential candidates for LT [19].The European Neuroendocrine Society (2012) recommends that LT should be considered in “selected patients” with a low index of proliferation (Ki-67) and no extrahepatic spread of the tumor [20]. In Brazil, LT is recommended in patients with unresectable liver metastases, resectable primary NET, and no extrahepatic tumor. Such patients receive a MELD score of exception points and therefore have faster access to transplant. Our patient had a welldifferentiated endocrine tumor with low mitotic index. He had no recurrence after 90 months of LT. Cholangiocarcinoma represents the second most common malignant hepatobiliary neoplasm. CC can be divided in intrahepatic, hilar and distal. While surgical treatment offers the best chance of cure with 5-year survival rates of 20%-45%, this is only achieved in about 20% of patients since most cases present in the form of unresectable disease [21]. The initial results for LT for CC were very poor, mainly due to a lack of adequate patient selection. Some centers have explored LT in patients with unresectable tumor confined to the hepatic hilum and more recently for patients with “very early” (single tumor of 2 cm) intrahepatic cholangiocarcinoma (iCC) [22,23]. Mayo Clinic group reported their experience with neoadjuvant chemoradiation followed by LT in hilar cholangiocarcinoma. In this study, they compared those patients undergoing a resection approach alone against those that underwent neoadjuvant therapy in addition to LT. The LT group achieved better overall survival at 1 (92% vs 82%), 3 (82% vs 48%), and 5 years (82% vs 21%) compared to the resection group. Importantly, all the patients underwent LT were deemed to be unresectable [24]. ICCs represent 5%-10% of all CCs. A Spanish consortium reported a series of 29 patients who were found to
MONT`ALVERNE PIERRE, VERAS, ESMERALDO ET AL
have iCCs exclusively in their explants. In these series, patients with “very early” iCCs did not present tumor recurrence and their long-term survival at 5 years was 73%. However, the number of patients in that study was limited [25]. In Brazil, cholangiocarcinoma remains an absolute contraindication to LT. Our present study reports 2 patients with incidentally detected cholangiocarcinoma in explants. One patient had multifocal disease and died 2 months after LT. The other patient had an iCC and did not use neoadjuvant chemoradiation. So far, the patient had no recurrence (7 months after LT). CONCLUSION
Liver transplantation could be a component of treatment for some non-hepatocellular malignancies in a subset patient mainly with hepatic epithelioid hemangioendothelioma, cholangiocarcinoma, and neuroendocrine tumor. However, further research is needed to better define inclusion criteria. Transplantation should not be utilized as it does not improve the dismal prognosis of angiosarcoma. REFERENCES [1] Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693e9. [2] Eghtesad B, Aucejo F. Liver transplantation for malignancies. J Gastrointest Cancer 2014;45:353e62. [3] Haberal Reyhan N. Liver transplant for nonhepatocellular carcinoma malignancy. Exp Clin Transplant 2017;15:69e73. [4] Reichman TW, Bhati CS, Battula NR. Obtaining optimal long-term outcomes from liver transplantation for hepatocellular cancer. Dig Dis Sci 2019;64:976e84. [5] Chapman WC, Klintmalm G, Hemming A, et al. Surgical treatment of hepatocellular carcinoma in North America: can hepatic resection still be justified? J Am Coll Surg 2015;220:628e37. [6] Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394e403. [7] Hsu CY, Liu PH, Lee YH, et al. Using serum alphafetoprotein for prognostic prediction in patients with hepatocellular carcinoma: what is the most optimal cutoff? PLoS One 2015;10: 1e12. [8] Bioulac-Sage P, Laumonier H, Laurent C, Blanc JF, Balabaud C. Benign and malignant vascular tumors of the liver in adults. Semin Liver Dis 2008;28:302e14. [9] Mani H, Van Thiel DH. Mesenchymal tumors of the liver. Clin Liver Dis 2001;5:219e57. [10] Castaldo ET, Pinson CW. Liver transplantation for nonhepatocellular carcinoma malignancy. HPB 2007;9:98e103. [11] Lerut J. Liver transplantation and vascular tumours. Proceedings of the 7th World Congress of the International HepatoPancreato-Biliary Association. Edinburgh, UK: IHPBA; 2006. 2006. Rochester, MN. [12] Madariaga JR, Marino IR, Karavias DD, et al. Long-term results after liver transplantation for primary hepatic epithelioid hemangioendothelioma. Ann Surg Oncol 1995;2:483e7. [13] Zhuang B, Li W, Chen Z-F, Cao C-J, Xie X-Y, Xie X-H. Multiple cavernous hemangiomas of the lung and liver mimicking metastasis. Medicine (Baltimore) 2018;97:e13509. https://doi.org/ 10.1097/MD.0000000000013509. [14] Orlando G, Adam R, Mirza D, et al. Hepatic hemangiosarcoma: an absolute contraindication to liver transplantation-the
NON-HEPATOCELLULAR CARCINOMA MALIGNANCY European Liver Transplant Registry experience. Transplantation 2013;95:872e7. [15] Husted TL, Neff G, Thomas MJ, Gross TG, Woodle ES, Buell JF. Liver transplantation for primary or metastatic sarcoma to the liver. Am J Transplant 2006;6:392e7. [16] Kim HR, Rha SY, Cheon SH, Roh JK, Park YN, Yoo NC. Clinical features and treatment outcomes of advanced stage primary hepatic angiosarcoma. Ann Oncol 2009;20:780e7. [17] Tran Minh M, Mazzola A, Perdigao F, Charlotte F, Rousseau G, Conti F. Primary hepatic angiosarcoma and liver transplantation: radiological, surgical, histological findings and clinical outcome. Clin Res Hepatol Gastroenterol 2018;42:17e23. [18] Kunz PL, Reidy-Lagunes D, Anthony LB, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas 2013;42:557e77. [19] Mazzaferro V, Pulvirenti A, Coppa J. Neuroendocrine tumors metastatic to the liver: how to select patients for liver transplantation? J Hepatol 2007;47:460e6. [20] Pavel ME, Baudin E, Couvelard A, et al. ENETS consensus guidelines for the management of patients with liver and others
5 distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2012;95:157e76. [21] Singh MK, Facciuto ME. Current management of cholangiocarcinoma. Mt Sinai J Med 2012;79:232e45. [22] Sudan D, DeRoover A, Chinnakotla S, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant 2002;2: 774e9. [23] Sapisochin G, Facciuto M, Rubbia-Brandt L, et al. Liver transplantation for “very early” intrahepatic cholangiocarcinoma: international retrospective study supporting a prospective assessment. Hepatology 2016;64:1178e88. [24] Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005;242:451e8. [25] Sapisochin G, Rodríguez de Lope C, Gastaca M, et al. “Very early” intrahepatic cholangiocarcinoma in cirrhotic patients: should liver transplantation be reconsidered in these patients? Am J Transplant 2014;14:660e7.
ABSTRACT Background. Liver transplantation has become an effective treatment for selected patients with hepatocellular carcinoma with excellent outcomes. More recent reports have described improved outcomes in liver transplantation in a subset of patients with other malignancies like hilar cholangiocarcinoma, unresectable hepatic epithelioid hemangioendothelioma and hepatic metastasis from neuroendocrine tumors. However, hepatic angiosarcoma remains an absolute contraindication to liver transplantation because of the poor outcome. Objectives. The present study aims to describe liver transplantation for nonhepatocellular carcinoma malignancy. Methods. A retrospective analysis of patients and review of the literature was performed. Results. A total of 5 patients with non-hepatocellular carcinoma malignancy on explants histopathologic findings were identified. They presented hepatic epithelioid hemangioendothelioma (1), neuroendocrine tumor (1), angiosarcoma (1) and cholangiocarcinoma (2). The mean length of follow-up was 22.8 37.67 (range, 2-90 months). Of 5 patients evaluated, 3 patients remain with stable graft function. Conclusion. Future investigations are necessary to redefine the indications of liver transplantations to treat non-hepatocellular carcinoma malignancy and its limitation.
L
IVER transplantation (LT) represents the best treatment in patients with decompensated cirrhosis, unresectable primary hepatic malignancies and acute liver failure in which spontaneous recovery is not anticipated. Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, and in a selected group of patients with cirrhosis, who fulfill the Milan criteria, liver transplantation offers the most reasonable expectation for curative treatment. These criteria, introduced by Mazzaferro in 1996, were as follows: (1) single tumor diameter less than 5 cm; (2) not more than 3 foci of tumor, each one not exceeding 3 cm; (3) no angioinvasion; and (4) no extrahepatic involvement, demonstrated a 5-year recurrence-free survival rate of 83% [1]. This favorable result could expand the LT as a therapeutic option for other malignancies of the liver such as hepatic epithelioid hemangioendothelioma (HEHE), hepatoblastoma,
ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, XX, 1e5 (2019)
unresectable liver metastases due to neuroendocrine tumors, cholangiocarcinoma (CC), sarcomas and recently colorectal metastatic lesions. The apparent limitation of expanding this treatment to a larger group of patients is the organ shortage. Therefore, the indications for LT for non-hepatocellular malignancy and its limitation will continue to be redefined through future investigations [2,3]. MATERIAL AND METHODS This study was conducted at the Liver Transplant Division of the General Hospital of Fortaleza (HGF, Fortaleza, Brazil). We
*Address correspondence to Alessandra Maria Mont’Alverne Pierre, Rua Coronel Alves Teixeira, 1578 Joaquim Távora, Fortaleza CE 60130-001, Ceara, Brazil. Tel: (085)34578085. E-mail: [email protected] 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.09.001
1
2
MONT`ALVERNE PIERRE, VERAS, ESMERALDO ET AL Table 1. Demographic and Epidemiologic Characteristics of the Population Studied (N [ 5)
No
Diagnosis of Non-HCC Malignancy before LT
Age at LT (y)
Sex
Causes of LT
1 2
33 55
Male Male
3 4 5
69 63 30
Male Male Female
Epithelioid hemangioendothelioma Unresectable liver metastases due to neuroendocrine tumor Cryptogenic cirrhosis Hepatitis C virus cirrhosis Primary sclerosing cholangitis cirrhosis
Yes Yes No No No
Explanted Liver
Epithelioid hemangioendothelioma Unresectable liver metastases due to neuroendocrine tumor Incidentally angiosarcoma Incidentally cholangiocarcinoma Incidentally cholangiocarcinoma
Abbreviation: HCC, hepatocellular carcinoma.
retrospectively analyzed the hospital records to evaluate our liver transplant receptors between December 2009 and July 2018 for the presence of non-hepatocellular malignancy by focusing on explants histopathologic findings. The following parameters were studied in all patients: age at transplantation, sex, indication for LT, primary immunosuppression, explants tumor characteristics, recurrence-free survival after LT, recurrent cancer treatment, overall survival after LT and cause of death. The diagnosis of malignancy was established by explants histopathologic findings. Initial immunosuppression was based on calcineurin inhibitors (tacrolimus), prednisone (until the third month after LT), supplemented with mycophenolate sodium or mammalian target of rapamycin inhibitor (mTOR) (everolimus) according to our actual study protocol. Modifications in doses or compounds were done individually, dependent on the clinical course.
Follow-up Our patients were examined according to our protocol, which includes liver function tests, routine blood tests and routine monitoring blood levels of tacrolimus and everolimus once a week in the first month, every 14 days from the second to the third month, every month from the fourth to the sixth month and then every 3 months. Bone scintigraphy and chest and abdominal computed tomography (CT) were performed whenever necessary and every 6 months from LT to the second year and then every year until 5 years after LT. Results were expressed as mean standard deviation. Statistical analyses were performed with SPSS software version 20 (IBM, Armonk, NY, United States).
RESULTS Patients’ Characteristics
From December 2009 to July 2018, 379 patients received an orthotopic liver transplant in our institution. A total of 5 patients with non-hepatocellular carcinoma malignancy on explants histopathologic findings were identified.
The demographic data of patients are shown in Table 1. Five patients were included, 80% men and mean age of 50 17. The indications for LT were due hepatic epithelioid hemangioendothelioma (n ¼ 1), unresectable liver metastases due to neuroendocrine tumors (n ¼ 1), cryptogenic cirrhosis (n ¼ 1), hepatitis C (n ¼ 1) and primary sclerosing cholangitis (n ¼ 1). The recipients’ explanted livers showed hepatic epithelioid hemangioendothelioma, neuroendocrine tumor, angiosarcoma, cholangiocarcinoma, and cholangiocarcinoma, respectively. Immunosuppression
All patients received triple-therapy-based immunosuppression with an initial calcineurin inhibitor (tacrolimus) in combination with prednisone (tapered within 3 months after LT) and everolimus (n ¼ 4) or mycophenolate sodium (n ¼ 1) as listed in Table 2. One patient changed mycophenolate mofetil to everolimus after cancer diagnosis in explant, and another patient was converted to mycophenolate mofetil due to dyslipidemia. Modifications in doses were done individually, and always the use of lower doses was preferred, thus reducing adverse effects associated with such drugs. No patient had an episode of biopsy-proven acute cellular rejection. Explant Tumor Characteristics
Patient 1: A 33-year-old man underwent LT due to HEFE, and a multifocal epithelioid proliferation was identified. Immunohistochemical staining positive for cytokeratin 7 and CD 31 in explant. Patient 2: A 55-year-old man had a midgut neuroendocrine tumor (ileum) and underwent surgical resection, enteroanastomosis, and lymphadenectomy. Biopsy revealed 2.7 1.6 cm neuroendocrine well-differentiated G3 tumor
Table 2. Primary and Secondary Immunosuppressive Regimens of the Population Studied (N [ 5) Immunosuppressive Regimens No
1 2 3 4 5
Primary
Secondary
Rejection
TAC, EVR, PD TAC, EVR, PD TAC,MMS, PD TAC, EVR, PD TAC, EVR, PD
Nc TAC,MMS TAC, EVR, PD Nc Nc
No No No No No
Last TAC Serum Concentration (Co)
2.6 4.3 2.3 3.6 3.2
ng/mL ng/mL ng/mL ng/mL ng/mL
Abbreviations: EVR, everolimus; MMS, mycophenolate sodium; Nc, no change; PD, prednisone; TAC, tacrolimus
Last EVR Serum Concentration (Co)
3.7 ng/mL ————— 2.5 ng/mL 2.0 ng/mL 2.0 ng/mL
NON-HEPATOCELLULAR CARCINOMA MALIGNANCY
with a Ki 67 proliferation index of 2% and no angiolymphatic invasion. Eight months later, he presented with multiple large liver metastases with no other spread to a secondary organ. The patient was submitted to transarterial chemoembolization and somatostatin analogue, but a contrast-enhanced CT showed multiple bilateral lesions in the liver, thus he underwent LT. Explant histopathological features confirmed diagnosis (NET). There were 4 nodules (the largest 13 11 cm) with cribriform tumor structure and low mitotic index. Patient 3: A 69-year-old man had decompensated cryptogenic cirrhosis leading to LT. He was classified ChildPugh C with 11 points, and his Model for End-Stage Liver Disease (MELD) score was 29. The explanted liver revealed a 1.2 cm tumor with a spindle cell pattern, high-grade nuclear atypia and immunohistochemical staining positive for CD34. Therefore, angiosarcoma was confirmed. Patient 4: A 63-year-old man underwent LT due to decompensated cirrhosis (hepatitis (C) and hepatocellular carcinoma. He was classified Child-Pugh B with 7 points, and despite a MELD score of 10, he was prioritized for HCC. The diagnosis of HCC was made before LT with CT and magnetic resonance imaging. Explant featured 3 lesions (the largest 3 2 cm) with well demarcated, firm, desmoplastic reaction, moderately differentiated adenocarcinoma G2, and no vascular invasion. Immunohistochemical staining positive for cytokeratin 7, cytokeratin 19 and negative for GATA 3. Histopathologic findings resulted in a diagnosis of cholangiocarcinoma. There was no HCC on explant. Patient 5: A 30-year-old woman had cirrhosis and underwent LT due to primary sclerosing cholangitis (PSC) with no inflammatory bowel disease, Child-Pugh B with 8 points and a MELD score of 20. Explant revealed a 2.6 1.5 cm pale tumor, with well-demarcated, firm, moderately differentiated G2 cholangiocarcinoma and no vascular invasion.
OUTCOMES
The mean length of follow-up was 22.8 37.67 (range, 2-90 mo). Of 5 patients evaluated, 3 are still alive and remain with stable graft function. The primary diagnosis of these patients was hepatic epithelioid hemangioendothelioma, cholangiocarcinoma, and neuroendocrine tumor. The follow-up was respectively 5, 7, and 90 months. No recurrence was noted. The patient who underwent LT due to hepatitis C cirrhosis and cholangiocarcinoma was found in explant developed pulmonary sepsis 2 months after LT and died. Malignancy recurrence was detected radiologically in one patient 1 month after LT. He presented recurrent angiosarcoma metastatic to the lung. The proposed course of treatment involved palliative chemotherapy. The patient was administered paclitaxel. Six months after uneventful chemotherapy, he developed chronic anemia and died 10 months after LT.
3
DISCUSSION
Liver transplantation is an effective treatment for hepatocellular carcinoma, in selected patients whose tumor masses do not exceed the Milan criteria, providing excellent longterm survival. Although, different studies, comparing outcomes from hepatectomy and LT for primary HCC, have been shown that disease-free survival is superior when LT is considered, others show different results [4,5]. Considering that the Milan criteria are limited and that a significant proportion of HCC patients are not eligible for transplantation, other criteria have been proposed. The University of California San Francisco has shown considerable results while including patients with solitary tumor with less than 6.5 cm, or 3 nodules with the largest lesion with 4.5 cm and total tumor diameter less than 8 cm [6] .The incorporation of tumor markers such as alpha fetoprotein in the inclusion criteria for HCC LT also has been proposed [7]. The decision to perform liver transplantation in a patient with non-HCC malignancy relies on the survival probabilities with LT. Vascular tumors of the liver in adult patients are a heterogeneous group with different behavior that includes cavernous hemangioma, a common benign tumor; epithelioid hemangioendothelioma, an enigmatic tumor with unpredictable malignant behavior but usually lowgrade malignant tumor and angiosarcoma, a very aggressive tumor [8,9]. Hepatic epithelioid hemangioendothelioma are bilobar tumors in almost all cases. Chemotherapy and radiation appear to offer little benefit. Resection is usually indicated, but the extensive multifocal nature of the disease can make surgical resection difficult and has made LT a more attractive option [10,11]. A retrospective study of 16 patients with HEHE showed survival 100%, 88%, and 71% at 1, 3, and 5 years, respectively. The presence of extrahepatic disease at the time of transplantation did not affect survival time [12]. In Brazil, LT is recommended to patients with unresectable HEHE and no extrahepatic spread of the tumor. They receive a MELD score of exception points and therefore have faster access to transplant. Our patient presented with multifocal HEHE and no extrahepatic disease before LT. To date, he is still alive with no recurrence and in a good clinical condition. Primary angiosarcoma is a rare malignant neoplasm and accounts for 2% of all primary tumors of the liver. In the United States the prevalence varies from .14 to 0.25 per million [13]. Thorotrast and its use in angiography, arsenic and vinyl chloride monomer in addition to androgenic anabolic steroids are frequently listed as risk [14,15]. Due to the characteristic of the aggressive tumor and the delay in diagnosis, the prognosis is very poor [16]. A retrospective study of 22 patients with angiosarcoma submitted to LT reported to the European Liver Transplant Registry, showed a median overall survival of 6 months and no patient survived for more than 2 years after LT. The use of an
4
mTOR inhibitor as an immunosuppressive treatment after LT has been suggested in many clinical cases, but this conversion does not inhibit the development of tumor metastases [17]. Compared to the above data, our present study reports a patient with incidental angiosarcoma in explant histopathologic findings and with poor prognosis. Immunosuppression was based on mTOR (everolimus). The recurrence occurred one month after LT and the patient survived for only ten months. Unacceptable survival and recurrence rates currently prohibit the use of LT in hepatic angiosarcoma. Neuroendocrine tumors are a group of tumors that originate in several locations, including the gastrointestinal tract, lung and pancreas [18]. In general, neuroendocrine tumors originating from the gastrointestinal tract are slowgrowing and are often discovered in a metastatic phase. Surgical resection for hepatic metastasis in a patient with NET, if possible, is the primary line treatment option. However, if metastases are limited to the liver, LT is a viable treatment option. Metastatic liver disease from NET is considered the only indication for LT for a metastatic cancer [2]. Thus, only patients with tumors presenting with biologically favorable features, such as limited bulk and absence of systemic disease are potential candidates for LT [19].The European Neuroendocrine Society (2012) recommends that LT should be considered in “selected patients” with a low index of proliferation (Ki-67) and no extrahepatic spread of the tumor [20]. In Brazil, LT is recommended in patients with unresectable liver metastases, resectable primary NET, and no extrahepatic tumor. Such patients receive a MELD score of exception points and therefore have faster access to transplant. Our patient had a welldifferentiated endocrine tumor with low mitotic index. He had no recurrence after 90 months of LT. Cholangiocarcinoma represents the second most common malignant hepatobiliary neoplasm. CC can be divided in intrahepatic, hilar and distal. While surgical treatment offers the best chance of cure with 5-year survival rates of 20%-45%, this is only achieved in about 20% of patients since most cases present in the form of unresectable disease [21]. The initial results for LT for CC were very poor, mainly due to a lack of adequate patient selection. Some centers have explored LT in patients with unresectable tumor confined to the hepatic hilum and more recently for patients with “very early” (single tumor of 2 cm) intrahepatic cholangiocarcinoma (iCC) [22,23]. Mayo Clinic group reported their experience with neoadjuvant chemoradiation followed by LT in hilar cholangiocarcinoma. In this study, they compared those patients undergoing a resection approach alone against those that underwent neoadjuvant therapy in addition to LT. The LT group achieved better overall survival at 1 (92% vs 82%), 3 (82% vs 48%), and 5 years (82% vs 21%) compared to the resection group. Importantly, all the patients underwent LT were deemed to be unresectable [24]. ICCs represent 5%-10% of all CCs. A Spanish consortium reported a series of 29 patients who were found to
MONT`ALVERNE PIERRE, VERAS, ESMERALDO ET AL
have iCCs exclusively in their explants. In these series, patients with “very early” iCCs did not present tumor recurrence and their long-term survival at 5 years was 73%. However, the number of patients in that study was limited [25]. In Brazil, cholangiocarcinoma remains an absolute contraindication to LT. Our present study reports 2 patients with incidentally detected cholangiocarcinoma in explants. One patient had multifocal disease and died 2 months after LT. The other patient had an iCC and did not use neoadjuvant chemoradiation. So far, the patient had no recurrence (7 months after LT). CONCLUSION
Liver transplantation could be a component of treatment for some non-hepatocellular malignancies in a subset patient mainly with hepatic epithelioid hemangioendothelioma, cholangiocarcinoma, and neuroendocrine tumor. However, further research is needed to better define inclusion criteria. Transplantation should not be utilized as it does not improve the dismal prognosis of angiosarcoma. REFERENCES [1] Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693e9. [2] Eghtesad B, Aucejo F. Liver transplantation for malignancies. J Gastrointest Cancer 2014;45:353e62. [3] Haberal Reyhan N. Liver transplant for nonhepatocellular carcinoma malignancy. Exp Clin Transplant 2017;15:69e73. [4] Reichman TW, Bhati CS, Battula NR. Obtaining optimal long-term outcomes from liver transplantation for hepatocellular cancer. Dig Dis Sci 2019;64:976e84. [5] Chapman WC, Klintmalm G, Hemming A, et al. Surgical treatment of hepatocellular carcinoma in North America: can hepatic resection still be justified? J Am Coll Surg 2015;220:628e37. [6] Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394e403. [7] Hsu CY, Liu PH, Lee YH, et al. Using serum alphafetoprotein for prognostic prediction in patients with hepatocellular carcinoma: what is the most optimal cutoff? PLoS One 2015;10: 1e12. [8] Bioulac-Sage P, Laumonier H, Laurent C, Blanc JF, Balabaud C. Benign and malignant vascular tumors of the liver in adults. Semin Liver Dis 2008;28:302e14. [9] Mani H, Van Thiel DH. Mesenchymal tumors of the liver. Clin Liver Dis 2001;5:219e57. [10] Castaldo ET, Pinson CW. Liver transplantation for nonhepatocellular carcinoma malignancy. HPB 2007;9:98e103. [11] Lerut J. Liver transplantation and vascular tumours. Proceedings of the 7th World Congress of the International HepatoPancreato-Biliary Association. Edinburgh, UK: IHPBA; 2006. 2006. Rochester, MN. [12] Madariaga JR, Marino IR, Karavias DD, et al. Long-term results after liver transplantation for primary hepatic epithelioid hemangioendothelioma. Ann Surg Oncol 1995;2:483e7. [13] Zhuang B, Li W, Chen Z-F, Cao C-J, Xie X-Y, Xie X-H. Multiple cavernous hemangiomas of the lung and liver mimicking metastasis. Medicine (Baltimore) 2018;97:e13509. https://doi.org/ 10.1097/MD.0000000000013509. [14] Orlando G, Adam R, Mirza D, et al. Hepatic hemangiosarcoma: an absolute contraindication to liver transplantation-the
NON-HEPATOCELLULAR CARCINOMA MALIGNANCY European Liver Transplant Registry experience. Transplantation 2013;95:872e7. [15] Husted TL, Neff G, Thomas MJ, Gross TG, Woodle ES, Buell JF. Liver transplantation for primary or metastatic sarcoma to the liver. Am J Transplant 2006;6:392e7. [16] Kim HR, Rha SY, Cheon SH, Roh JK, Park YN, Yoo NC. Clinical features and treatment outcomes of advanced stage primary hepatic angiosarcoma. Ann Oncol 2009;20:780e7. [17] Tran Minh M, Mazzola A, Perdigao F, Charlotte F, Rousseau G, Conti F. Primary hepatic angiosarcoma and liver transplantation: radiological, surgical, histological findings and clinical outcome. Clin Res Hepatol Gastroenterol 2018;42:17e23. [18] Kunz PL, Reidy-Lagunes D, Anthony LB, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas 2013;42:557e77. [19] Mazzaferro V, Pulvirenti A, Coppa J. Neuroendocrine tumors metastatic to the liver: how to select patients for liver transplantation? J Hepatol 2007;47:460e6. [20] Pavel ME, Baudin E, Couvelard A, et al. ENETS consensus guidelines for the management of patients with liver and others
5 distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2012;95:157e76. [21] Singh MK, Facciuto ME. Current management of cholangiocarcinoma. Mt Sinai J Med 2012;79:232e45. [22] Sudan D, DeRoover A, Chinnakotla S, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant 2002;2: 774e9. [23] Sapisochin G, Facciuto M, Rubbia-Brandt L, et al. Liver transplantation for “very early” intrahepatic cholangiocarcinoma: international retrospective study supporting a prospective assessment. Hepatology 2016;64:1178e88. [24] Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005;242:451e8. [25] Sapisochin G, Rodríguez de Lope C, Gastaca M, et al. “Very early” intrahepatic cholangiocarcinoma in cirrhotic patients: should liver transplantation be reconsidered in these patients? Am J Transplant 2014;14:660e7.