Introduction

Melanoma is a disease of melanocytes with the vast majority of cases being of cutaneous in origin [1]. Malignant melanoma (MM) is an aggressive malignancy with an unpredictable metastatic pattern, with the most common organs involved being the lungs, bone, lymph nodes, liver and brain [2]. Liver metastasis are detected in approximately 10–20% of patients diagnosed with MM, however, liver dysfunction is exceedingly uncommon [3]. Survival rates vary between the subtypes of melanoma, with mucosal and uveal portending a poor prognosis, however, 5-year survival rates in those diagnosed with stage IV cutaneous melanoma has been previously documented at 34.3% [4]. Further to this, liver failure secondary to MM is rare with the literature limited to case reports and is associated with a dismal prognosis [5]. We present the case of a 59-year-old male who presented with hepatitis who subsequently progressed into acute hepatic failure secondary to metastatic melanoma of cutaneous origin.

Case report

A 59-year-old male presented to our institution with a 7-day history of right upper quadrant pain, myalgia, nausea and subjective fevers. He had a history notable for cutaneous actinic keratosis and cutaneous melanoma in situ localised on the upper back, previously excised one year prior to presentation with clear surgical margins on histopathological assessment of the post-operative specimen. He was on no regular medications. Examination on admission demonstrated right upper quadrant and epigastric tenderness. Biochemical evaluation revealed liver enzyme derangement with an aspartate transferase (AST) of 353 U/L, alanine aminotransferase (ALT) of 616 U/L, alkaline phosphatase (ALP) of 329 U/L and gamma-glutamyl transferase (GGT) of 507 U/L. Bilirubin was elevated to 23 mmol/L. Lactate dehydrogenase (LDH) and ferritin were elevated to 1640 U/L and 2350 ug/L, respectively. His INR was 1.4 and prothrombin time was elevated to 19 s. The remainder of his biochemical assessment for acute liver dysfunction was normal.

Abdominal ultrasound demonstrated a coarse liver echotexture with nodularity along with splenic nodularity (Fig. 1A). Subsequent magnetic resonance cholangiopancreatography (MRCP) revealed a diffusely abnormal and heterogenous liver with five focal lesions along with multiple thoracic and lumbar bone lesions (Fig. 1B). Inpatient FDG-PET/CT scan revealed intensely FDG avid left axillary, peripancreatic and portocaval lymphadenopathy (Fig. 1C). Further to this, splenic nodules along with numerous FDG avid bone lesions were identified. His liver demonstrated global diffusely increased uptake along with superimposed intense foci throughout.

Fig. 1
figure 1

A Abdominal ultrasound demonstrating hepatic nodularity; B MRCP demonstrating a diffusely abnormal and heterogenous liver; C FDG-PET/CT scan revealed intensely FDG avid left axillary, peripancreatic and portocaval lymphadenopathy

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On day 5 of the patient’s admission, core biopsy was performed of the left axillary lymph node. Histopathological analysis of the left axillary lymph node core biopsy revealed discohesive nests of epithelioid cells showing enlarged, hyperchromatic nuclei, nucleoli and many containing pigment on hematoxylin and eosin staining (Fig. 1A). Subsequent immunohistochemistry demonstrated positive staining for MART1 (Fig. 1B), along with SOX10 and HMB45. A diagnosis of metastatic melanoma was made with an acute liver injury secondary to hepatic infiltration. Targeted mutational analysis using next generation sequencing identified a NRAS Q61L gene mutation (Fig. 2).

Fig. 2
figure 2

A Hematoxylin and eosin staining of left axillary lymph node core biopsy demonstrating discohesive nests of epithelioid cells showing hyperchromatic nuclei and nucleoli. Prominent pigment is present. B Immunohistochemistry (IHC) for MART1 is positive consistent with metastatic melanoma

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The patient was commenced on dual immunotherapy with nivolumab and ipilimumab. Two days after immunotherapy commencement the patient deteriorated with decompensated liver failure secondary to hepatic infiltration, with the development of hepatorenal syndrome and ascites. His AST and ALT increased to 2900 IU/L and 1180 IU/L, respectively. Serum bilirubin was also significantly elevated to 100 mmol/L, along with LDH to 14,600 U/L (Fig. 3). Despite treatment with intravenous terlipressin and intensive care admission, the patient deteriorated with refractory encephalopathy and type one hepatorenal syndrome. A palliative approach was adopted. The patient died 17 days post initial presentation.

Fig. 3
figure 3

Line graph depicting clinical and biochemical deterioration during inpatient admission. ICI – immune checkpoint inhibitor; HRS-1 – hepatorenal syndrome type 1. AST – aspartate aminotransferase; ALT – alanine aminotransferase; Alk. Phos.—alkaline phosphatase; GGT—Gamma Glutamyl Transferase; LDH – Lactate dehydrogenase

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Discussion

Melanoma, although only making up a small subset of cutaneous malignancies, accounts for a significant amount of morbidity and mortality. This is reportedly secondary to the high metastatic propensity of the tumour [6]. Liver metastasis secondary to malignant melanoma is relatively common, however, substantial replacement of liver by tumour resulting in impaired liver function is rare and limited to case reports [3, 7,8,9,10,11,12,13,14,15,16,17,18,19,20]. This case shares similarities with previously published cases, namely the rapid progression to liver failure and subsequent death,

Histologically, melanoma dissemination is characterized by leukemoid tumour infiltration of the liver sinusoids leading to obstruction, hepatocellular death, and liver failure [19]. Clinically, hepatic infiltration of MM is difficult to distinguish from other primary causes of hepatitis. Biochemical signs that increase suspicion of an underlying malignant aetiology include mild to moderately elevated serum aminotransferases, ALP and bilirubin levels, while an elevated lactate dehydrogenase (LDH) has been associated with tumour involvement previously [5]. LDH elevation has been previously identified as an ominous sign in the context of acute liver failure secondary to metastatic malignancy, as demonstrated in the presented case [8, 11, 17]. This is perceived to be secondary to extensive cellular ischaemia and necrosis, or related to release of LDH from the tumor cells themselves [8]. Imaging features are usually non-specific, however, hepatomegaly without defined nodular lesions is a usual manifestation of diffuse hepatic melanoma infiltration [20].

Previously, the pathophysiology of acute liver failure in the context of MM was postulated to be secondary to hepatic ischemia arising from sinusoidal infiltration and vessel invasion. This is supported in the case of the presented patient by the dramatic rise in serum aminotransferases and LDH, as well as the presence of pain [11]. It has also been hypothesised that simple replacement of the liver parenchyma by melanoma itself results in rapid liver failure [8].

Clinically, patients present with non-specific symptoms such as pain, fatigue, nausea and anorexia. The prognosis of the disease is exceedingly poor with life expectancy ranging from days to months based on previous case reports, while the diagnosis is commonly made posthumously due to severe coagulopathy precluding liver biopsy [20]. Treatment focuses on targeting the underling malignancy with a view to stabilise hepatic function to prevent further decompensation, however, given the degree of liver involvement in the presented case, it was deemed that despite immunotherapy, rapid progression of his underlying acute hepatic failure was the likely cause of death.

This case highlights an exceedingly uncommon cause of acute hepatic failure which initially presented with features suggestive of hepatitis. A potential diagnosis of immune checkpoint inhibitor hepatitis was flagged as a differential diagnosis, however, due to the coagulopathy, a biopsy was not pursued. MM is an extremely rare cause of acute liver failure with the literature limited to case reports. In such cases, the prognosis is poor, as demonstrated with the presented patient. Future research should aim to focus on the identification of early non-invasive biomarkers that could assist in aiding clinicians in the early diagnosis of hepatic metastasis in the case of metastatic melanoma. Early identification of hepatic disease in metastatic melanoma should prompt clinicians to implement or escalate therapy given the poor prognosis associated with progression to hepatic failure. In the case of rapid liver failure secondary to MM, the pathophysiology of the disease process is a relatively unknown entity given the lack of published literature pertaining to it. With earlier identification of metastatic disease, perhaps future studies could aim to focus on the tumor microenvironment in the liver to determine the processes that occur at a cellular level that drives progression to liver failure. In the case of abdominal pain with progressive liver function derangement and subsequent acute hepatic failure, metastatic malignancy, including but not limited to MM, should be considered as a potential diagnosis given its associated poor prognosis.