Hepatocellular carcinoma with cutaneous metastases

Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia Correspondence: Dr Alan Weiss, Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6. Telephone 604-877-6000 ext 2740, fax 604-877-0585, e-mail aweiss@bccancer.bc.ca Received for publication December24, 2007. Accepted April 17, 2008 S Rueben, D Owen, P Lee, A Weiss. Hepatocellular carcinoma with cutaneous metastases. Can J Gastroenterol 2009;23(1):23-25.

C utaneous metastases from hepatocellular carcinoma (HCC) are very rare.Previous reports have described these skin lesions to be rapidly growing nodules found mostly on the face, scalp, chest and shoulders.The lesions appear singly, or in multiples as firm, painless, nonulcerative, reddish nodules that are approximately 1 cm to 2.5 cm in diameter (1,2).Others are larger, with either a pyogenic granuloma-like (1) or a hemangiomatous character (3) that bleed extremely easily and grow rapidly.Two cases of skin metastases from HCC are reported.Both patients had a lesion resembling a reddish nodule, while one patient also presented with a larger pyogenic granuloma-like lesion.

Case 1
In 2004, A 60-year-old Middle-Eastern man initially presented with a history of mild fatigue and right upper quadrant pain.His workup revealed a large, solitary, inhomogeneous, extremely vascular lesion within the right lobe of the liver measuring approximately 13 cm × 15 cm.His carcinoembryonic antigen (CA) tumour marker level was 1.1 µg/L and his alphafetoprotein (AFP) level was 4.9 µg/L, both within the normal range.Further laboratory studies showed a total bilirubin level of 5 µmol/L (normal 0 µmol/L to 18 µmol/L), aspartate aminotransferase 95 U/L (normal 10 U/L to 38 U/L), alanine aminotransferase 32 U/L (normal 20 U/L to 65 U/L), alkaline phosphatase 237 IU/L (normal 50 IU/L to 160 IU/L), total serum protein 72 g/L (normal 62 g/L to 82 g/L), hemoglobin 111 g/L (normal 135 g/L to 175 g/L), platelet count 331×10 9 /L (normal 125×10 9 /L to 350×10 9 /L), white blood cell count 6.9×10 9 /L (normal 4×10 9 /L to 10×10 9 /L), lactate dehydrogenase 150 U/L (normal 90 U/L to 210 U/L) and an international normalized ratio of 1.23 (normal 0.9 to 1.2).The patient had a history of hepatitis B. His appetite was good and his weight was stable.He had no gastrointestinal-related symptoms and no significant medical history.
A needle core biopsy showed mild chronic hepatitis.The mass, however, had the characteristics of HCC and the patient was treated with chemoembolization followed by a resection of the tumour.A follow-up computed tomography (CT) scan of the abdomen showed no recurrent or residual tumour.There were no known metastases at the time.
The patient was asymptomatic until April 2006, when he developed several skin lesions located on his left nostril, his forehead and the right side of his neck.The lesions on his forehead and neck appeared as reddish nodules approximately 0.5 cm in size in diameter.The lesion on his left nostril however, grew rapidly with a nodular surface that was extremely vascular and bled easily.The patient initially mistook the nodules to be mosquito bites and did not seek medical attention until July 2006.
In July 2006, a biopsy performed on a left neck lesion of the patient showed features consistent with metastatic HCC.The tumour cells were positive for keratin and hepatocyte-specific antigens but negative for S100 protein.
Due to the increasing size of the left nostril lesion, which in July 2006 measured approximately 2 cm × 2 cm × 2 cm (Figure 1), a resection was performed by an otolaryngologist and again the pathology showed metastatic HCC (Figure 2).The tumour filled the stroma and had both trabecular and pseudoglandular patterns.Focal bile production was present.
The patient also presented with progressive weakness and numbness in both his left arm and left leg.A CT scan of his brain performed in July 2006 showed a solitary right frontal and parietal lobe mass measuring 2.5 cm × 2.8 cm.A right rolandic craniotomy and tumour resection was performed with the pathology again consistent with metastatic HCC.Further investigations showed pulmonary and bone metastases.Chemotherapy was considered, but due to the fact that the patient had developed a gluteal abscess and a weakened condition, chemotherapy was not initiated.Consequently, patient received supportive therapy and subsequently died.

Case 2
The second patient was a 76-year-old woman known to be hepatitis B-positive and routinely monitored by abdominal ultrasound.In February 2005, an ultrasound revealed three solid lesions that were consistent with hepatoma.A blood test showed an elevated tumour marker AFP level of 16 µg/L (normal less than 11 µg/L).Her laboratory findings showed a white blood cell count of 11.6×10 9 /L (normal 4×10 9 /L to 10×10 9 /L), hemoglobin of 107 g/L (normal 135 g/L to 175 g/L), platelet count of 434×10 9 /L (normal 125×10 9 /L to 350×10 9 /L), a direct bilirubin of 60 µmol/L (normal 0 µmol/L to 5 µmol/L), aspartate aminotransferase 82 U/L (normal 10 U/L to 38 U/L), alanine aminotransferase 90 U/L (normal 20 U/L to 65 U/L), gammaglutamyl transpeptidase 161 U/L (normal 10 U/L to 55 U/L), alkaline phosphatase 173 IU/L (normal 50 IU/L to 200 IU/L), lactate dehydrogenase 226 U/L (normal 90 U/L to 210 U/L) and an international normalized ratio of 1.27 (normal 0.9 to 1.2).A subsequent CT scan confirmed these findings showing two lesions within segments II/III (diameter, 5 cm) and V/VIII (diameter 2 cm), as well as changes consistent with cirrhosis.The patient was treated with alcohol ablation of the left lesion because resection was thought to be associated with a high risk of liver decompensation due to the cirrhotic appearance of the liver and the large volume of liver that would need to be resected.The lesion on the patient's right side was to be treated once the patient had recovered from the procedure.During the procedure, however, a biopsy was taken of the surrounding tissue and revealed cirrhosis.At the time, the patient was asymptomatic with no significant medical history.She did, however, have a positive family history of liver cancer.
A follow-up CT scan showed several new hypervascular nodules scattered throughout the liver as well as an elevated AFP level of 14 µg/L.Subsequently, a chemoembolization of the right hepatic artery was performed in December 2005.There was also evidence of portal vein thrombosis and cholelithiasis.Subsequent imaging showed successful chemoembolization of the right lesion.
At the end of May 2006, the patient noticed a lump on her right upper and lower eyelid that was causing significant tearing (Figure 3).She was seen by an ophthalmologist.The lesion was initially thought to be a stye.However, because local treatments did not help, a biopsy was performed in July 2006.The pathology revealed metastatic adenocarcinoma consistent with metastatic HCC (Figure 4).The patient's condition had deteriorated.She had visible lumpiness of both the upper and lower eyelid.She reported a loss of appetite as well as severe dyspnea and orthopnea.She presented with fever, ascites, pedal edema and crackles in her right thorax.A CT scan of her thorax showed diffuse pulmonary nodules consistent with metastases.The patient's condition continued to deteriorate; she received supportive care and subsequently died.

DiSCUSSiOn
Metastases to the skin from internal malignancies are very uncommon (4).The most common cancers that metastasize to the skin are of pulmonary or breast origin.The most common site of HCC metastases are the lungs, followed by the periportal lymph nodes and the bones (5).Skin metastases from HCC, however, are very rare.In one study by Peters (6), skin metastases were shown to account for only 2.7% of cirrhotic HCCs and no cases in noncirrhotic HCC.Otherwise, only a few case reports exist.Of these case reports, some describe cutaneous metastases due to direct implantation from a procedure such as a biopsy or ablation treatment of HCC.One report (7) described a nodule presenting at the injection site of a percutaneous ethanol injection therapy performed three months previously.These direct deposits are, of course, different in etiology than distant metastatic disease, which occured in the present two cases.Previous reports (1,2) have described these skin lesions to be rapidly growing nodules found mostly on the face, scalp, chest and shoulders.The lesions appear singly or in multiples as firm, painless, nonulcerative, reddish nodules which are approximately 1 cm to 2.5 cm in diameter.Other lesions are larger and have been described morphologically to resemble either a pyogenic granuloma (1) or a hemangioma (3), both of which bleed easily and grow rapidly.Recently, a skin lesion was even described as being 'abscess-like' (8).While both patients reported and presented with lesions resembling reddish nodules, one patient presented with a larger vascular lesion that resembled a pyogenic granuloma.Biopsies from both patients diagnosed metastatic HCC.
Cutaneous metastasis can present as the first clinical sign of HCC (8-10).Both of our patients, however, presented with cutaneous metastases approximately one year following diagnosis of HCC.In both patients, the skin lesions were the first sign of metastatic disease, although further follow-up revealed other metastatic sites.
Because cutaneous metastases are a very uncommon manifestation of HCC, the present two cases should increase awareness of their existence.The possibility of skin metastasis should be considered in HCC patients who present with skin nodules, and the diagnosis should be confirmed by biopsy.

Figure 1 )Figure 2 )
Figure 1) Large nodule on the left nostril resembling a pyogenic granuloma Figure 2) Biopsy of tumour from left nostril showing a dermal deposit of hepatocellular carcinoma Hepatocellular carcinoma with cutaneous metastasesCan J Gastroenterol Vol 23 No 1 January 2009 25

Figure 4 )Figure 3 )
Figure 4) High-power view of hepatocelluar carcinoma showing a predominately solid pattern with compressed sinusoids and ill-formed psueudoacini