LETTER
TO THE
EDITOR
Liver Transplantation for Liver Malignancies in Wilson’s Disease: Two Novel Cases ilson disease (WD) is a rare autosomal recessive disorder of copper (Cu) metabolism that presents with hepatic, neurologic, or psychiatric disturbances. It typically begins with a presymptomatic period, during which Cu accumulation in the liver causes subclinical hepatitis and progresses to liver cirrhosis and development of neuropsychiatric symptoms. Liver disease consists of jaundice, autoimmune-type hepatitis, fulminanthepatic failure, or chronic liver disease leading to cirrhosis (1). Cirrhosis is commonly the basis of hepatocellular carcinoma (HCC) development, which has rarely been previously reported because of very few available series with long-term follow-up but perhaps should suggest increased vigilance (2). On the other hand, cholangiocarcinoma (CCC) appears to be extremely rare in this disease, with only five cases reported in the literature (2). Liver transplantation (LT) provides cure for WD in patients where medical therapy has failed or in those with advanced decompensated liver disease at initial evaluation (3). Its association with liver malignancies (LM) such as HCC and CCC has been scarcely documented. We herein report on two cases of coexistence of WD with LM, which have been successfully transplanted. The first patient is a 49-year-old woman with a 23-year history of WD and Child-Turcotte-Pugh B cirrhosis. During follow-up imaging, contrastenhanced computed tomography (CT) revealed four tumor lesions with a maximal diameter of 4.5 cm. Alphafetoprotein (AFP), carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9 were within normal range. Radiologic workup was accomplished using abdominal magnetic resonance imaging, thoracic CT, and bone scintigraphy according to our protocol (4), which has ruled out extrahepatic manifestations. Computed tomographyYguided
W
Transplantation
tumor biopsy set the diagnosis of multifocal HCC. The patient was listed for LT and underwent two sessions of transarterial-chemoembolization (TACE) as bridging therapy. She was transplanted 8 months later with a model for end-stage liver disease (MELD) score of 9. Histology confirmed the preoperative diagnosis of four HCC lesions with microvascular invasion (Fig. 1A). Two years after LT, she manifested a solitary lung metastasis, which was successfully resected. The second patient is a 48-yearold man with an 18-year history of WD and Child-Turcotte-Pugh B cirrhosis. During follow-up imaging, CT scan revealed two malignant focuses in segment VIII. To establish a diagnosis in that nodular cirrhotic liver, a CT-guided biopsy was performed. The presence of malignancy was confirmed without identifying its origin. AFP, CEA, and CA 19-9 were normal in repetitive measurements. Radiologic workup was accomplished by abdominal magnetic resonance imaging, thoracic CT, and bone scintigraphy, which have ruled out extrahepatic manifestations. As the lesions were highly suggestive of HCC within the Milan criteria, he was listed for LT and underwent a session of TACE as bridging therapy. Eleven months after TACE, he was successfully transplanted with MELD score of 27. Final histology revealed, in contrast to the preoperative assumption, a bifocal CCC without vascular invasion (Fig. 1B). Follow-up studies revealed no evidence of tumor recurrence. Posttransplantation treatment included corticosteroids; tacrolimus, which was switched to m-TOR inhibitor (sirolimus) after 3 months; and mycophenolate mofetil in both patients according to the protocol of our department. Post-LT follow-up encompassed abdominal and thoracic CTevery 3 months during the first year, every 6 months during the second year, and yearly thereafter. Both patients remain in good general condition 32 and
& Volume 97, Number 6, March 27, 2014
24 months after LT, respectively, and receive no chelating agent. An increased risk of LM is recognized in some forms of metabolic liver disease. Interestingly, although tumors are rare in WD (3), HCCs and CCCs have been described in several case reports as well as in recent retrospective studies of WD patients, suggesting higher frequency of these malignancies in WD patients than in the control population (2). In contrast to our patient, in most of the reported cases, the LM was incidentally diagnosed in the pathologic specimen after death for WD-induced liver failure (2). Various attempts have been made to ascertain which patients with WD should be considered for LT (3). Patients with WD should enroll close follow-up with imaging examinations, as AFP measurement alone is not reliable for exclusion of LM. Fulminant liver failure and disease refractory to medical treatments consists the current indications for LT in WD. The risk of LM is not to ignore and could consist additional indication for LT. These patients should be eventually listed earlier for LT, irrelevant to liver function status. According to our restricted experience with transplanted LM in WD, WD patients may benefit from earlier listing/LT, and LT may provide acceptable results even in the case of CCC.
Spiridon Vernadakis1,2 Demetrios Moris2 Georgios C. Sotiropoulos1 1
Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Germany 2 Transplantation Unit, Laikon General Hospital, University of Athens Athens Greece www.transplantjournal.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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& Volume 97, Number 6, March 27, 2014
FIGURE 1. a. HCC in Wilson cirrhosis. A: HE staining, B: Immunohistochemical staining against hepar-1, C: Immunohistochemical staining against CK-7. Original magnification, 100. b. CCC in Wilson cirrhosis. A: Hematoxylin-eosin staining, B: Immunohistochemical staining against hepar-1, C: Immunohistochemical staining against CK-7. Original magnification, 100. The authors declare no funding or conflicts of interest. Address correspondence to: Demetrios Moris, MD, Anastasiou Gennadiou 56, 11474, Athens, Greece. E-mail: [email protected] S.V. and D.M. contributed equally. S.V. collected the data and wrote the article. D.M. analyzed the data and contributed important reagents. G.C.S. collected the data and designed and supervised the manuscript. Received November 22 2013. Accepted 17 December 2013.
Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9706-e35 DOI: 10.1097/TP.0000000000000026
3.
REFERENCES 1. 2.
Lalioti V, Sandoval I, Cassio D, et al. Molecular pathology of Wilson’s disease: a brief. J Hepatol 2010; 53: 1151. Merle U, Schaefer M, Ferenci P, et al. Clinical presentation, diagnosis and long-term
4.
outcome of Wilson’s disease: a cohort study. Gut 2007; 56: 115. Moini M, Mistry P, Schilsky ML. Liver transplantation for inherited metabolic disorders of the liver. Curr Opin Organ Transplant 2010; 15: 269. Sotiropoulos GC, Lang H, Nadalin S, et al. Liver transplantation for hepatocellular carcinoma: University Hospital Essen experience and metaanalysis of prognostic factors. J Am Coll Surg 2007; 205: 661.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
TO THE
EDITOR
Liver Transplantation for Liver Malignancies in Wilson’s Disease: Two Novel Cases ilson disease (WD) is a rare autosomal recessive disorder of copper (Cu) metabolism that presents with hepatic, neurologic, or psychiatric disturbances. It typically begins with a presymptomatic period, during which Cu accumulation in the liver causes subclinical hepatitis and progresses to liver cirrhosis and development of neuropsychiatric symptoms. Liver disease consists of jaundice, autoimmune-type hepatitis, fulminanthepatic failure, or chronic liver disease leading to cirrhosis (1). Cirrhosis is commonly the basis of hepatocellular carcinoma (HCC) development, which has rarely been previously reported because of very few available series with long-term follow-up but perhaps should suggest increased vigilance (2). On the other hand, cholangiocarcinoma (CCC) appears to be extremely rare in this disease, with only five cases reported in the literature (2). Liver transplantation (LT) provides cure for WD in patients where medical therapy has failed or in those with advanced decompensated liver disease at initial evaluation (3). Its association with liver malignancies (LM) such as HCC and CCC has been scarcely documented. We herein report on two cases of coexistence of WD with LM, which have been successfully transplanted. The first patient is a 49-year-old woman with a 23-year history of WD and Child-Turcotte-Pugh B cirrhosis. During follow-up imaging, contrastenhanced computed tomography (CT) revealed four tumor lesions with a maximal diameter of 4.5 cm. Alphafetoprotein (AFP), carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9 were within normal range. Radiologic workup was accomplished using abdominal magnetic resonance imaging, thoracic CT, and bone scintigraphy according to our protocol (4), which has ruled out extrahepatic manifestations. Computed tomographyYguided
W
Transplantation
tumor biopsy set the diagnosis of multifocal HCC. The patient was listed for LT and underwent two sessions of transarterial-chemoembolization (TACE) as bridging therapy. She was transplanted 8 months later with a model for end-stage liver disease (MELD) score of 9. Histology confirmed the preoperative diagnosis of four HCC lesions with microvascular invasion (Fig. 1A). Two years after LT, she manifested a solitary lung metastasis, which was successfully resected. The second patient is a 48-yearold man with an 18-year history of WD and Child-Turcotte-Pugh B cirrhosis. During follow-up imaging, CT scan revealed two malignant focuses in segment VIII. To establish a diagnosis in that nodular cirrhotic liver, a CT-guided biopsy was performed. The presence of malignancy was confirmed without identifying its origin. AFP, CEA, and CA 19-9 were normal in repetitive measurements. Radiologic workup was accomplished by abdominal magnetic resonance imaging, thoracic CT, and bone scintigraphy, which have ruled out extrahepatic manifestations. As the lesions were highly suggestive of HCC within the Milan criteria, he was listed for LT and underwent a session of TACE as bridging therapy. Eleven months after TACE, he was successfully transplanted with MELD score of 27. Final histology revealed, in contrast to the preoperative assumption, a bifocal CCC without vascular invasion (Fig. 1B). Follow-up studies revealed no evidence of tumor recurrence. Posttransplantation treatment included corticosteroids; tacrolimus, which was switched to m-TOR inhibitor (sirolimus) after 3 months; and mycophenolate mofetil in both patients according to the protocol of our department. Post-LT follow-up encompassed abdominal and thoracic CTevery 3 months during the first year, every 6 months during the second year, and yearly thereafter. Both patients remain in good general condition 32 and
& Volume 97, Number 6, March 27, 2014
24 months after LT, respectively, and receive no chelating agent. An increased risk of LM is recognized in some forms of metabolic liver disease. Interestingly, although tumors are rare in WD (3), HCCs and CCCs have been described in several case reports as well as in recent retrospective studies of WD patients, suggesting higher frequency of these malignancies in WD patients than in the control population (2). In contrast to our patient, in most of the reported cases, the LM was incidentally diagnosed in the pathologic specimen after death for WD-induced liver failure (2). Various attempts have been made to ascertain which patients with WD should be considered for LT (3). Patients with WD should enroll close follow-up with imaging examinations, as AFP measurement alone is not reliable for exclusion of LM. Fulminant liver failure and disease refractory to medical treatments consists the current indications for LT in WD. The risk of LM is not to ignore and could consist additional indication for LT. These patients should be eventually listed earlier for LT, irrelevant to liver function status. According to our restricted experience with transplanted LM in WD, WD patients may benefit from earlier listing/LT, and LT may provide acceptable results even in the case of CCC.
Spiridon Vernadakis1,2 Demetrios Moris2 Georgios C. Sotiropoulos1 1
Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Germany 2 Transplantation Unit, Laikon General Hospital, University of Athens Athens Greece www.transplantjournal.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
e35
e36
www.transplantjournal.com
Transplantation
& Volume 97, Number 6, March 27, 2014
FIGURE 1. a. HCC in Wilson cirrhosis. A: HE staining, B: Immunohistochemical staining against hepar-1, C: Immunohistochemical staining against CK-7. Original magnification, 100. b. CCC in Wilson cirrhosis. A: Hematoxylin-eosin staining, B: Immunohistochemical staining against hepar-1, C: Immunohistochemical staining against CK-7. Original magnification, 100. The authors declare no funding or conflicts of interest. Address correspondence to: Demetrios Moris, MD, Anastasiou Gennadiou 56, 11474, Athens, Greece. E-mail: [email protected] S.V. and D.M. contributed equally. S.V. collected the data and wrote the article. D.M. analyzed the data and contributed important reagents. G.C.S. collected the data and designed and supervised the manuscript. Received November 22 2013. Accepted 17 December 2013.
Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9706-e35 DOI: 10.1097/TP.0000000000000026
3.
REFERENCES 1. 2.
Lalioti V, Sandoval I, Cassio D, et al. Molecular pathology of Wilson’s disease: a brief. J Hepatol 2010; 53: 1151. Merle U, Schaefer M, Ferenci P, et al. Clinical presentation, diagnosis and long-term
4.
outcome of Wilson’s disease: a cohort study. Gut 2007; 56: 115. Moini M, Mistry P, Schilsky ML. Liver transplantation for inherited metabolic disorders of the liver. Curr Opin Organ Transplant 2010; 15: 269. Sotiropoulos GC, Lang H, Nadalin S, et al. Liver transplantation for hepatocellular carcinoma: University Hospital Essen experience and metaanalysis of prognostic factors. J Am Coll Surg 2007; 205: 661.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
