Clin J Gastroenterol (2010) 3:327–331 DOI 10.1007/s12328-010-0181-x
CASE REPORT
Acute hepatic failure secondary to extensive hepatic replacement by metastatic amelanotic melanoma: an autopsy case report Takayuki Fusasaki • Ryoichi Narita • Masaaki Hiura • Shintaro Abe • Akinari Tabaru • Ryosuke Hino • Atsuji Matsuyama • Shohei Shimajiri Yoshiki Tokura • Yasuyuki Sasaguri • Masaru Harada
•
Received: 13 April 2010 / Accepted: 15 September 2010 / Published online: 23 October 2010 Ó Springer 2010
Abstract Metastatic malignant melanoma (MM) of the liver evolving into acute hepatic failure is a rare occurrence. We describe the case of an 82-year-old man with a history of MM on the left thumb treated with amputation and chemotherapy 40 months previously. On admission, he had abdominal pain, weight loss, lethargy and jaundice. Radiologic investigations such as enhanced computed tomography and abdominal ultrasound failed to establish an etiologic diagnosis. A liver biopsy revealed amelanotic melanoma cells diffusely infiltrating the hepatic parenchyma. His liver injury progressed and the patient died of hepatic failure on the 13th hospital day. Autopsy revealed [70% infiltration by metastatic amelanotic melanoma in the liver.
T. Fusasaki R. Narita (&) M. Hiura S. Abe A. Tabaru M. Harada Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan e-mail: [email protected] R. Hino Y. Tokura Department of Dermatology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan A. Matsuyama First Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan S. Shimajiri Y. Sasaguri Second Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
Keywords Amelanotic melanoma Liver metastasis Acute hepatic failure
Introduction Although liver metastases are common and diagnosed in 10–20% of patients with malignant melanoma (MM) [1], it is unusual for substantial replacement of the liver by tumor cells to impair liver function. Acute hepatic failure (AHF) secondary to metastatic MM of the liver appears to be rare [2–8]. We report here the case of a patient with MM who developed AHF. In this case, abdominal ultrasonography (US) and computerized tomography (CT) showed a hepatomegaly but could not detect any tumorous lesion. A liver biopsy disclosed diffuse infiltration of amelanotic melanoma cells. An autopsy revealed [70% infiltration by metastatic amelanoma melanoma in the liver.
Case report An 82-year-old man was admitted to our hospital after experiencing jaundice, nausea and vomiting with general malaise for 2 weeks. Previously he had been healthy and no epidemiologic features of hepatitis were found in his history. He had a past history of MM 40 months earlier. In 2006, he had ulcers (12 9 17 mm and 5 9 5 mm) on the tip of the left thumb, which were diagnosed as MM by skin biopsy. Lymph node swelling was found in the left axillary sentinel node. A lymph node biopsy was performed and pathologic finding showed metastasis of MM. The pathologic stage was T4bN1bM0 stage IIIC, and the clinical subtype was acral lentiginous melanoma. His left thumb was amputated but left axillary lymph node dissection was
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not performed at the patient’s request. The lesion on the left thumb was histologically diagnosed as MM. Some finely granular black pigment was present with MM cells. Ki67 showed nuclear staining of approximately 12% of the MM cells (Fig. 1). Systemic postoperative chemotherapy with DAV-Feron treatment (dacarbazine, nimustine, vincristine, and interferon-beta) promptly induced lymph nodule regression. Five cycles of chemotherapy were administered over a period of 1 year and local recurrence did not occur. Screening for metastasis was periodically performed by CT scan and no metastasis was detected in the abdomen (Fig. 2a). The patient remained well until February 2009, when he complained of abdominal pain, weight loss, lethargy, and jaundice. On admission, he was not disoriented, and vital signs were unremarkable. Neither pigmentated lesion nor superficial nodular lesion was observed. The liver was firm and palpable at 5 cm below the epigastrium. Admission laboratory values are shown in Table 1. An abdominal US and CT scan revealed heterogeneous liver and hepatosplenomegaly without focal mass (Fig. 2b–d). A CT scan showed a small amount of ascites and a slightly depressed inferior vena cava due to the enlarged liver. Although various examinations were performed, the cause of the liver failure was unclear. We considered other tests such as contrast-enhanced US or contrast-enhanced
Fig. 1 The left thumb after amputation and histologic features of the left thumb. a The ulcer and pigmented lesion of the top of left thumb are observed. b Histologic features of the left thumb show a malignant melanoma (MM). Malignant polygonal and spindle cells are seen (H&E, 910). The insert is a high magnification (H&E, 920). c Some finely granular black pigment was present in the MM cells (arrows) (H&E, 940). d Findings of Ki67 staining of MM cells (reactivity approximately 12%)
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magnetic resonance imaging (MRI); however, the patient’s clinical course continued to deteriorate after admission and we could not perform these examinations. A percutaneous liver biopsy was performed on the 7th hospital day which demonstrated a proliferation of tumor cells infiltrating into the hepatic intrasinusoidal spaces (Fig. 3a, b). Although few brown pigments were found, the tumor cells were immunoreactive to HMB-45 and S-100 proteins (Fig. 3c, d). There was a slight increase in aminotransferase and serum lactate dehydrogenase; however, chemotherapy was not performed because of the rapid clinical deterioration. He became markedly jaundiced (serum bilirubin rose to 18.6 mg/dL) and showed encephalopathy on the 11th hospital day. The patient died of hepatic failure on the 13th hospital day. At autopsy the liver weighed 3,700 g (Fig. 4a). The cut surfaces were extensively replaced by small gray tumor nodules up to 3 cm in diameter (Fig. 4b). Microscopic examination revealed[70% liver infiltration by amelanotic melanoma cells. The diagnosis was verified by an immunohistochemical phenotype of S-100 and HMB-45 positive cells (Fig. 4c). Ki67-labeling index of the melanoma cells was 13.7% (Fig. 4d). Small metastatic nodules of tumor were detected in the heart, lung, duodenum, gall bladder, small intestine, rectum and mesenterium. These were all micrometastatic except for the hepatic metastases. Left axillary lymph node metastasis was not seen.
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329
Fig. 2 Abdominal computed tomography (CT) scan and an ultrasonography (US) of the liver. a Abdominal CT scan 6 months before admission revealed a normal appearance of the liver and spleen. b Abdominal US on admission shows hepatomegaly with no remarkable foci in the liver. The liver edge was dull and liver parenchyma was heterogenous. c, d Contrast-enhanced CT scan on admission shows hepatomegaly and no remarkable foci in the liver. No para-aortic lymph nodes are noted. Spleen is normal size. c Early phase; d delayed phase
Table 1 Laboratory findings on admission
Hematology
Viral marker
WBC
8,400/lL
IgM-HA Ab
(-)
RBC
324 9 104/lL
HBsAg
(-)
Hb Plt
10.3 g/dL 14.1 9 104/lL
HBcAb IgM-HBcAb
(-) (-)
Coagulation
WBC white blood cell, RBC red blood cell, Hb hemoglobin, Ht hematocrite, Plt platelet, PT prothrombin, APTT activated partial thromboplastin time, FDP fibrinoid degradation product, Alb alubumin, AST alanine aminotransferase, ALT aspartate aminotransferase, LDH lactate dehydrogenase, ALP alkaline phosphatase, GGT gamma-glutamyl transferase, BUN blood urea nitrogen, Cre creatinine, ANA antinuclear antibody, AMA antimitochondrial antibody, LKM-1 liver/kidney microsome type 1
HBV-DNA
(-)
PT
48.00%
HCV Ab
1.1 S/CO
APTT
52.1 s
HCV-RNA
(-)
FDP
9.1 lg/mL
EB VCA IgM
(-)
EB VCA IgG
(?)
Chemistry TP
6.1 g/dL
EBNA antibody
(?)
Alb
1.8 g/dL
Cytomegalo IgM
(-)
Total bilirubin
11.8 mg/dL
Cytomegalo IgG
(?)
Direct bilirubin
8.1 mg/dL
Immunology
AST
93 IU/L
CRP
1.79 mg/dL
ALT
51 IU/L
IgG
2,714 mg/dL
LDH
431 IU/L
IgM
111 mg/dL
ALP
845 IU/L
ANA
(-)
GGP BUN
364 IU/L 22.0 mg/dL
AMA Anti-LKM-1-Ab
(-) 14.1
Cre
0.73 mg/dL
Discussion The liver is a common site of the metastatic spread of cancer. Derangement of hepatocellular function is unusual until terminal deterioration, although there have been a number of case reports describing the occurrence of AHF secondary to infiltration in the liver by malignant cell populations, as observed in the present patient [9, 10].
These cases have involved liver metastasis from breast cancer, gastric cancer, colon cancer, lung cancer, pancreatic cancer, lymphomas and leukemias [10]. To our knowledge, AHF associated with MM was reported in 7 cases [2–8]. Two cases were of unknown primary origin [6, 7]; the other 5 cases were metastatic [2–5, 8]. Three of 4 autopsy cases revealed that, as in the present case, the liver was almost completely occupied by melanoma cells [2, 3, 5].
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Fig. 3 Pathologic view of the liver biopsy. a Low power view of the biopsy (H&E, 94). b High power view of the biopsy. Malignant spindle cells are seen. No melanin pigment is seen (H&E, 9200). c Immunohistochemical staining of the liver specimen with HMB-45. HMB-45 antibody stains malignant melanocytes with a brown chromogen. d Immunohistochemical staining of the liver biopsy specimen with S-100. S-100 antibody stains malignant melanocytes with a brown chromogen
Fig. 4 a Autopsy findings of the liver. The liver is remarkably enlarged, with a weight of 3,700 g. b The cut surfaces were extensively replaced by gray tumor nodules up to 3 cm in diameter (arrows). c Amelanotic MM cells remarkably increased around the portal area and in the sinusoid and the liver parenchyma is atrophic. Microscopic section of the liver showing diffuse infiltrate of amelanotic melanoma cells with islands of surviving hepatic tissue (arrowheads) (H&E, 9100). d Findings of Ki67 staining of amelanotic melanoma cells (reactivity approximately 13.7%)
There have been no reported cases with an amelanotic melanoma. Most cases with AHF associated with MM rapidly progressed to fulminant hepatic failure and death [8]. Malignant cell infiltration or tumor lysis syndrome is important for AHF associated with MM [8]. In the present case the mechanisms of rapid liver failure seemed to be related to simple replacement of the liver by melanoma rather than a process of parenchymal necrosis [8]. Although some patients with AHF associated with MM had significant elevation of serum lactate dehydrogenase
123
(LDH) and aminotransferase, these levels were lower in our patient than those of previous reported cases. Elevated serum LDH often appears to denote hepatic involvement in metastatic disease. Its degree of elevation may represent extensive cellular ischemia and necrosis secondary to compromised vascular supply from the pressure effect of invading tumor cells. The tumor cells themselves may also have released a large amount of LDH, further elevating the level. These elevations may occasionally be associated with extensive parenchymal infarction [9]. The only mild
Clin J Gastroenterol (2010) 3:327–331
elevation in our patient’s LDH level was not understood completely. In our case, the autopsy finding showed mild necrosis in the liver tissue. In the present case, metastasis appeared suddenly 3 years later. Late recurrence of melanoma is not uncommon with 5- and 10-year recurrence rates being 25 and 34%, respectively [11]. Recurrence of melanoma up to 24 years after the initial diagnosis has been reported [12]. Hepatic metastases of MM are often hypervascular [13, 14]. Metastases are usually multiple and have a variable contrast enhancement pattern either homogeneously or in a ring pattern on a CT scan [13, 14]. It is unclear why we could not detect tumor nodules in US or enhanced CT. In most AHF cases associated with MM, imaging studies failed to reveal classical metastatic deposits [2–6]; however, contrast-enhanced CT and contrast-enhanced MRI could detect massive tumor in a small number of cases, such as widespread coagulation necrosis of the remaining parenchyma or portal vein occluded by tumor [7, 8]. We did not perform Kupffer cell functional examination such as contrast-enhanced US, which may have the possibility to reveal a focal mass in the liver. In most cases, the induction of AHF by diffuse hepatic melanoma infiltration has been demonstrated by histologic studies at biopsy or autopsy [2–6]. A histologic study is important for diagnosis of AHF associated with MM. In the present case, black pigment was not observed in the cytoplasm of the tumor cells in the liver biopsy. Immunohistochemistry of melanoma antigens such as HMB-45 and S-100 protein was essential for the diagnosis of amelanotic MM in the present case [15]. The frequency of malignant amelanotic melanoma is assessed at less than 10% of all MM cases [16]. Malignant amelanotic melanoma designates a tumor which is composed of histologically authentic melanoblasts with complete absence of melanin pigment [16]. Total absence of melanin in these cells was observed not only at the primary site but also at its metastatic locations [16]. A melanoblast in an amelanotic tumor has potential biochemical activity to produce melanin but the rapid cell differentiation causes the cells to lose their capacity to produce and store pigment [16]. Therefore, cells of amelanotic melanoma grow rapidly and are more primitive. A previous study reported that amelanosis was one of the prognostic factors of MM [16]. The primary site of this patient was pigment positive, but the metastatic site was pigment negative. On the other hand, we examined the proliferative rate in both the primary site and the liver by Ki67 antibody, which is expressed throughout the growth phase of the cell cycle [17]. A previous study reported that Ki67 proliferative activity is an independent prognostic factor in MM [17]. In the present case, however, both the primary site and the liver showed a positive index less than 20%.
331
In summary, we report an unusual case of AHF, resulting from metastatic amelanotic melanoma replacing the liver after a long disease-free period. For this reason, in patients with a history of MM who present with AHF, malignant infiltration of tumor cells to the liver should be considered. Histologic examination is important for diagnosis in such patients.
References 1. Rose DM, Essner R, Hughes TM, Tang PC, Bilchik A, Wanek LA, Thompson JF, Morton DL. Surgical resection for metastatic melanoma to the liver: the John Wayne Cancer Institute and Sydney Melanoma Unit experience. Arch Surg. 2001;136:950–5. 2. Bouloux PM, Scott RJ, Goligher JE, Kindell C. Fulminant hepatic failure secondary to diffuse liver infiltration by melanoma. J R Soc Med. 1986;79:302–3. 3. Kaplan GG, Medlicott S, Culleton B, Laupland KB. Acute hepatic failure and multi-system organ failure secondary to replacement of the liver with metastatic melanoma. BMC Cancer. 2005;5:67. 4. Montero JL, Muntane J, de las Heras S, Ortega R, Fraga E, De la Mata M. Acute liver failure caused by diffuse hepatic melanoma infiltration. J Hepatol. 2002;37:540–1. 5. Rubio S, Barbero-Villares A, Reina T, Nieto S, Mendoza J, Garcia-Buey L. Rapidly-progressive liver failure secondary to melanoma infiltration. Gastroenterol Hepatol. 2005;28:619–21. 6. Shan GD, Xu GQ, Chen LH, Wang ZM, Jin EY, Hu FL, Li YM. Diffuse liver infiltration by melanoma of unknown primary origin: one case report and literature review. Intern Med. 2009;48: 2093–6. 7. Tanaka M, Watanabe S, Masaki T, Kurokohchi K, Kinekawa F, Inoue H, Uchida N, Kuriyama S. Fulminant hepatic failure caused by malignant melanoma of unknown primary origin. J Gastroenterol. 2004;39:804–6. 8. Te HS, Schiano TD, Kahaleh M, Lissoos TW, Baker AL, Hart J, Conjeevaram HS. Fulminant hepatic failure secondary to malignant melanoma: case report and review of the literature. Am J Gastroenterol. 1999;94:262–6. 9. Harrison HB, Middleton HM 3rd, Crosby JH, Dasher MN Jr. Fulminant hepatic failure: an unusual presentation of metastatic liver disease. Gastroenterology. 1981;80:820–5. 10. Rowbotham D, Wendon J, Williams R. Acute liver failure secondary to hepatic infiltration: a single centre experience of 18 cases. Gut. 1998;42:576–80. 11. Uchiyama S, Imamura N, Ohuchida J, Hiyoshi M, Nagano M, Marutsuka K, Akiyama Y, Chijiiwa K. Late recurrence of malignant melanoma in the duodenum. Hepatogastroenterology. 2008;55:1619–21. 12. Slattery E, O’Donoghue D. Metastatic melanoma presenting 24 years after surgical resection: a case report and review of the literature. Cases J. 2009;2:189. 13. Berman C, Reintgen D. Radiologic imaging in malignant melanoma: a review. Semin Surg Oncol. 1993;9:232–8. 14. Kalkman E, Baxter G. Melanoma. Clin Radiol. 2004;59:313–26. 15. Matusiak L, Bieniek A, Wozniak Z, Szepietowski JC. Amelanotic malignant melanoma in an acral location. Acta Dermatovenerol Alp Panonica Adriat. 2008;17:72–4. 16. Huvos AG, Shah JP, Goldsmith HS. A clinicopathologic study of amelanotic melanoma. Surg Gynecol Obstet. 1972;135:917–20. 17. Ramsay JA, From L, Iscoe NA, Kahn HJ. MIB-1 proliferative activity is a significant prognostic factor in primary thick cutaneous melanomas. J Invest Dermatol. 1995;105:22–6.
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CASE REPORT
Acute hepatic failure secondary to extensive hepatic replacement by metastatic amelanotic melanoma: an autopsy case report Takayuki Fusasaki • Ryoichi Narita • Masaaki Hiura • Shintaro Abe • Akinari Tabaru • Ryosuke Hino • Atsuji Matsuyama • Shohei Shimajiri Yoshiki Tokura • Yasuyuki Sasaguri • Masaru Harada
•
Received: 13 April 2010 / Accepted: 15 September 2010 / Published online: 23 October 2010 Ó Springer 2010
Abstract Metastatic malignant melanoma (MM) of the liver evolving into acute hepatic failure is a rare occurrence. We describe the case of an 82-year-old man with a history of MM on the left thumb treated with amputation and chemotherapy 40 months previously. On admission, he had abdominal pain, weight loss, lethargy and jaundice. Radiologic investigations such as enhanced computed tomography and abdominal ultrasound failed to establish an etiologic diagnosis. A liver biopsy revealed amelanotic melanoma cells diffusely infiltrating the hepatic parenchyma. His liver injury progressed and the patient died of hepatic failure on the 13th hospital day. Autopsy revealed [70% infiltration by metastatic amelanotic melanoma in the liver.
T. Fusasaki R. Narita (&) M. Hiura S. Abe A. Tabaru M. Harada Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan e-mail: [email protected] R. Hino Y. Tokura Department of Dermatology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan A. Matsuyama First Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan S. Shimajiri Y. Sasaguri Second Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
Keywords Amelanotic melanoma Liver metastasis Acute hepatic failure
Introduction Although liver metastases are common and diagnosed in 10–20% of patients with malignant melanoma (MM) [1], it is unusual for substantial replacement of the liver by tumor cells to impair liver function. Acute hepatic failure (AHF) secondary to metastatic MM of the liver appears to be rare [2–8]. We report here the case of a patient with MM who developed AHF. In this case, abdominal ultrasonography (US) and computerized tomography (CT) showed a hepatomegaly but could not detect any tumorous lesion. A liver biopsy disclosed diffuse infiltration of amelanotic melanoma cells. An autopsy revealed [70% infiltration by metastatic amelanoma melanoma in the liver.
Case report An 82-year-old man was admitted to our hospital after experiencing jaundice, nausea and vomiting with general malaise for 2 weeks. Previously he had been healthy and no epidemiologic features of hepatitis were found in his history. He had a past history of MM 40 months earlier. In 2006, he had ulcers (12 9 17 mm and 5 9 5 mm) on the tip of the left thumb, which were diagnosed as MM by skin biopsy. Lymph node swelling was found in the left axillary sentinel node. A lymph node biopsy was performed and pathologic finding showed metastasis of MM. The pathologic stage was T4bN1bM0 stage IIIC, and the clinical subtype was acral lentiginous melanoma. His left thumb was amputated but left axillary lymph node dissection was
123
328
not performed at the patient’s request. The lesion on the left thumb was histologically diagnosed as MM. Some finely granular black pigment was present with MM cells. Ki67 showed nuclear staining of approximately 12% of the MM cells (Fig. 1). Systemic postoperative chemotherapy with DAV-Feron treatment (dacarbazine, nimustine, vincristine, and interferon-beta) promptly induced lymph nodule regression. Five cycles of chemotherapy were administered over a period of 1 year and local recurrence did not occur. Screening for metastasis was periodically performed by CT scan and no metastasis was detected in the abdomen (Fig. 2a). The patient remained well until February 2009, when he complained of abdominal pain, weight loss, lethargy, and jaundice. On admission, he was not disoriented, and vital signs were unremarkable. Neither pigmentated lesion nor superficial nodular lesion was observed. The liver was firm and palpable at 5 cm below the epigastrium. Admission laboratory values are shown in Table 1. An abdominal US and CT scan revealed heterogeneous liver and hepatosplenomegaly without focal mass (Fig. 2b–d). A CT scan showed a small amount of ascites and a slightly depressed inferior vena cava due to the enlarged liver. Although various examinations were performed, the cause of the liver failure was unclear. We considered other tests such as contrast-enhanced US or contrast-enhanced
Fig. 1 The left thumb after amputation and histologic features of the left thumb. a The ulcer and pigmented lesion of the top of left thumb are observed. b Histologic features of the left thumb show a malignant melanoma (MM). Malignant polygonal and spindle cells are seen (H&E, 910). The insert is a high magnification (H&E, 920). c Some finely granular black pigment was present in the MM cells (arrows) (H&E, 940). d Findings of Ki67 staining of MM cells (reactivity approximately 12%)
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magnetic resonance imaging (MRI); however, the patient’s clinical course continued to deteriorate after admission and we could not perform these examinations. A percutaneous liver biopsy was performed on the 7th hospital day which demonstrated a proliferation of tumor cells infiltrating into the hepatic intrasinusoidal spaces (Fig. 3a, b). Although few brown pigments were found, the tumor cells were immunoreactive to HMB-45 and S-100 proteins (Fig. 3c, d). There was a slight increase in aminotransferase and serum lactate dehydrogenase; however, chemotherapy was not performed because of the rapid clinical deterioration. He became markedly jaundiced (serum bilirubin rose to 18.6 mg/dL) and showed encephalopathy on the 11th hospital day. The patient died of hepatic failure on the 13th hospital day. At autopsy the liver weighed 3,700 g (Fig. 4a). The cut surfaces were extensively replaced by small gray tumor nodules up to 3 cm in diameter (Fig. 4b). Microscopic examination revealed[70% liver infiltration by amelanotic melanoma cells. The diagnosis was verified by an immunohistochemical phenotype of S-100 and HMB-45 positive cells (Fig. 4c). Ki67-labeling index of the melanoma cells was 13.7% (Fig. 4d). Small metastatic nodules of tumor were detected in the heart, lung, duodenum, gall bladder, small intestine, rectum and mesenterium. These were all micrometastatic except for the hepatic metastases. Left axillary lymph node metastasis was not seen.
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329
Fig. 2 Abdominal computed tomography (CT) scan and an ultrasonography (US) of the liver. a Abdominal CT scan 6 months before admission revealed a normal appearance of the liver and spleen. b Abdominal US on admission shows hepatomegaly with no remarkable foci in the liver. The liver edge was dull and liver parenchyma was heterogenous. c, d Contrast-enhanced CT scan on admission shows hepatomegaly and no remarkable foci in the liver. No para-aortic lymph nodes are noted. Spleen is normal size. c Early phase; d delayed phase
Table 1 Laboratory findings on admission
Hematology
Viral marker
WBC
8,400/lL
IgM-HA Ab
(-)
RBC
324 9 104/lL
HBsAg
(-)
Hb Plt
10.3 g/dL 14.1 9 104/lL
HBcAb IgM-HBcAb
(-) (-)
Coagulation
WBC white blood cell, RBC red blood cell, Hb hemoglobin, Ht hematocrite, Plt platelet, PT prothrombin, APTT activated partial thromboplastin time, FDP fibrinoid degradation product, Alb alubumin, AST alanine aminotransferase, ALT aspartate aminotransferase, LDH lactate dehydrogenase, ALP alkaline phosphatase, GGT gamma-glutamyl transferase, BUN blood urea nitrogen, Cre creatinine, ANA antinuclear antibody, AMA antimitochondrial antibody, LKM-1 liver/kidney microsome type 1
HBV-DNA
(-)
PT
48.00%
HCV Ab
1.1 S/CO
APTT
52.1 s
HCV-RNA
(-)
FDP
9.1 lg/mL
EB VCA IgM
(-)
EB VCA IgG
(?)
Chemistry TP
6.1 g/dL
EBNA antibody
(?)
Alb
1.8 g/dL
Cytomegalo IgM
(-)
Total bilirubin
11.8 mg/dL
Cytomegalo IgG
(?)
Direct bilirubin
8.1 mg/dL
Immunology
AST
93 IU/L
CRP
1.79 mg/dL
ALT
51 IU/L
IgG
2,714 mg/dL
LDH
431 IU/L
IgM
111 mg/dL
ALP
845 IU/L
ANA
(-)
GGP BUN
364 IU/L 22.0 mg/dL
AMA Anti-LKM-1-Ab
(-) 14.1
Cre
0.73 mg/dL
Discussion The liver is a common site of the metastatic spread of cancer. Derangement of hepatocellular function is unusual until terminal deterioration, although there have been a number of case reports describing the occurrence of AHF secondary to infiltration in the liver by malignant cell populations, as observed in the present patient [9, 10].
These cases have involved liver metastasis from breast cancer, gastric cancer, colon cancer, lung cancer, pancreatic cancer, lymphomas and leukemias [10]. To our knowledge, AHF associated with MM was reported in 7 cases [2–8]. Two cases were of unknown primary origin [6, 7]; the other 5 cases were metastatic [2–5, 8]. Three of 4 autopsy cases revealed that, as in the present case, the liver was almost completely occupied by melanoma cells [2, 3, 5].
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Fig. 3 Pathologic view of the liver biopsy. a Low power view of the biopsy (H&E, 94). b High power view of the biopsy. Malignant spindle cells are seen. No melanin pigment is seen (H&E, 9200). c Immunohistochemical staining of the liver specimen with HMB-45. HMB-45 antibody stains malignant melanocytes with a brown chromogen. d Immunohistochemical staining of the liver biopsy specimen with S-100. S-100 antibody stains malignant melanocytes with a brown chromogen
Fig. 4 a Autopsy findings of the liver. The liver is remarkably enlarged, with a weight of 3,700 g. b The cut surfaces were extensively replaced by gray tumor nodules up to 3 cm in diameter (arrows). c Amelanotic MM cells remarkably increased around the portal area and in the sinusoid and the liver parenchyma is atrophic. Microscopic section of the liver showing diffuse infiltrate of amelanotic melanoma cells with islands of surviving hepatic tissue (arrowheads) (H&E, 9100). d Findings of Ki67 staining of amelanotic melanoma cells (reactivity approximately 13.7%)
There have been no reported cases with an amelanotic melanoma. Most cases with AHF associated with MM rapidly progressed to fulminant hepatic failure and death [8]. Malignant cell infiltration or tumor lysis syndrome is important for AHF associated with MM [8]. In the present case the mechanisms of rapid liver failure seemed to be related to simple replacement of the liver by melanoma rather than a process of parenchymal necrosis [8]. Although some patients with AHF associated with MM had significant elevation of serum lactate dehydrogenase
123
(LDH) and aminotransferase, these levels were lower in our patient than those of previous reported cases. Elevated serum LDH often appears to denote hepatic involvement in metastatic disease. Its degree of elevation may represent extensive cellular ischemia and necrosis secondary to compromised vascular supply from the pressure effect of invading tumor cells. The tumor cells themselves may also have released a large amount of LDH, further elevating the level. These elevations may occasionally be associated with extensive parenchymal infarction [9]. The only mild
Clin J Gastroenterol (2010) 3:327–331
elevation in our patient’s LDH level was not understood completely. In our case, the autopsy finding showed mild necrosis in the liver tissue. In the present case, metastasis appeared suddenly 3 years later. Late recurrence of melanoma is not uncommon with 5- and 10-year recurrence rates being 25 and 34%, respectively [11]. Recurrence of melanoma up to 24 years after the initial diagnosis has been reported [12]. Hepatic metastases of MM are often hypervascular [13, 14]. Metastases are usually multiple and have a variable contrast enhancement pattern either homogeneously or in a ring pattern on a CT scan [13, 14]. It is unclear why we could not detect tumor nodules in US or enhanced CT. In most AHF cases associated with MM, imaging studies failed to reveal classical metastatic deposits [2–6]; however, contrast-enhanced CT and contrast-enhanced MRI could detect massive tumor in a small number of cases, such as widespread coagulation necrosis of the remaining parenchyma or portal vein occluded by tumor [7, 8]. We did not perform Kupffer cell functional examination such as contrast-enhanced US, which may have the possibility to reveal a focal mass in the liver. In most cases, the induction of AHF by diffuse hepatic melanoma infiltration has been demonstrated by histologic studies at biopsy or autopsy [2–6]. A histologic study is important for diagnosis of AHF associated with MM. In the present case, black pigment was not observed in the cytoplasm of the tumor cells in the liver biopsy. Immunohistochemistry of melanoma antigens such as HMB-45 and S-100 protein was essential for the diagnosis of amelanotic MM in the present case [15]. The frequency of malignant amelanotic melanoma is assessed at less than 10% of all MM cases [16]. Malignant amelanotic melanoma designates a tumor which is composed of histologically authentic melanoblasts with complete absence of melanin pigment [16]. Total absence of melanin in these cells was observed not only at the primary site but also at its metastatic locations [16]. A melanoblast in an amelanotic tumor has potential biochemical activity to produce melanin but the rapid cell differentiation causes the cells to lose their capacity to produce and store pigment [16]. Therefore, cells of amelanotic melanoma grow rapidly and are more primitive. A previous study reported that amelanosis was one of the prognostic factors of MM [16]. The primary site of this patient was pigment positive, but the metastatic site was pigment negative. On the other hand, we examined the proliferative rate in both the primary site and the liver by Ki67 antibody, which is expressed throughout the growth phase of the cell cycle [17]. A previous study reported that Ki67 proliferative activity is an independent prognostic factor in MM [17]. In the present case, however, both the primary site and the liver showed a positive index less than 20%.
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In summary, we report an unusual case of AHF, resulting from metastatic amelanotic melanoma replacing the liver after a long disease-free period. For this reason, in patients with a history of MM who present with AHF, malignant infiltration of tumor cells to the liver should be considered. Histologic examination is important for diagnosis in such patients.
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