J Gastrointest Canc DOI 10.1007/s12029-015-9722-3

CASE REPORT

Clear Cell Cancer of the Liver Presenting with Pathological Humeral Fracture: a Case Report Mina S. Hanna 1 & Debasish Das 1

# Springer Science+Business Media New York 2015

Background Hepatocellular carcinoma is the fifth most common cancer and third leading cause of cancer mortality worldwide [1]. Risk factors for the development of HCC include Hepatitis B, liver cirrhosis due to any etiology, obesity, tobacco smoking and diabetes mellitus [2]. Most commonly, patients with HCC present with abdominal pain, fever of unknown etiology and weight loss or decompensation of known liver disease, while up to a quarter are diagnosed at an asymptomatic stage through surveillance [3]. Metastatic disease most commonly affects the lung, lymph nodes, adrenal glands and bone [4], and initial presentation with complications of metastases is uncommon. Most bony metastases affect the vertebral column followed by the pelvis, rib and skull, while metastases to distal sites such as the humerus are rare [5]. We present a case of a 70-year-old gentleman without previously known liver disease, who was diagnosed with metastatic hepatic clear cell carcinoma following presentation with right arm pain secondary to pathological right humeral shaft fracture.

Case Description A 70-year-old right-handed retired heavy goods vehicle driver presented to our local Accident and Emergency Department in * Mina S. Hanna [email protected] 1

Department of Gastroenterology, Kettering General Hospital, Rothwell Road, Kettering, Northants NN16 8UZ, UK

November 2013 with a 2-month history of intermittent right upper arm discomfort. His pain worsened following a fall onto his outstretched hand the week prior to presentation. His past medical history included type II diabetes, atrial fibrillation, chronic kidney disease (stage 3), hypertension, hypercholesterolemia and obesity. He was not known to have liver disease. At the time of presentation, he was taking metformin, furosemide, pravastatin, bisoprolol and lansoprazole. He was an ex-smoker of 20 pack years and consumed about 4 units of alcohol per week and denied any past history of alcohol excess. Clinical examination revealed an elevated BMI of 32. There was tenderness over the right humerus, but no neurovascular compromise in the right limb. Respiratory, cardiovascular and abdominal examination were unremarkable. X-ray of the right humerus revealed a pathological fracture of the right humeral shaft (Fig. 1a). Blood tests revealed a normocytic anaemia with haemoglobin 11.7 g/dL (reference range 13.0–18.0 g/dL) and a mean corpuscular volume (MCV) of 92.4 (reference range, 80–100 fL). Renal function tests were consistent with his known chronic kidney disease; urea 10.7 mmol/L (reference range 2.5–7.8 mmol/L) and creatinine 192 μmol/L (reference range 80–120 μmol/L, eGFR 32.1). Liver function tests, coagulation profile and corrected calcium levels were within the normal reference range. Subsequently, a bone scan was arranged which showed increased uptake of isotope in the right humerus that was consistent with the recent fracture but no significant uptake in the remainder of the bones Fig. 2. He subsequently underwent pinning of the right humeral shaft fracture (Fig. 1b) and reamings of the tumour were sent away for histology and immunostaining. Histology was consistent with metastatic clear cell carcinoma. The tumour cells showed strongly positive staining for the hepatocytic marker HepPar1 and a

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mixed attenuating lesion in relation to segment V/VI of the liver (Fig. 3). There was no evidence of biliary dilatation. No lesions were identified in the chest or other abdominal organs, and there was no evidence of lymphadenopathy. Acoustic radiation force impulse (ARFI) elastography was performed, which showed an increased liver mean propagation velocity of 2.99 m/s, consistent with stage IV liver fibrosis (liver cirrhosis) (Fig. 4). Serological screening for viral, autoimmune and metabolic causes of liver diseases was negative. A renal tract ultrasound showed bilateral normal-sized kidneys (9.5 and 10 cm, respectively) without evidence of focal lesions. Alpha fetoprotein levels were 18 (reference range 0–7), while CA125, CA-199 and PSA were within the normal range. Following discussion at our local upper gastrointestinal multidisciplinary meeting, the lesion was not felt to be resectable due to its size, cirrhosis of the background liver with significant risk of decompensation after surgery and medical comorbidities of the patient. He was referred to the regional oncology team for consideration of systemic palliative chemotherapy with sorafenib as well as regional radiotherapy to the right humerus to improve pain. He was administered a single fraction of 8 Gy radiotherapy to the humerus. In view of his poor performance status of 3 and numerous comorbidities, the Fig. 1 X-ray showing pathological right humeral shaft fracture (a) and X-ray post pinning of the right humeral shaft fracture (b)

canalicular pattern of staining for polyclonal CEA, strongly supporting a diagnosis of hepatocellular carcinoma. A non-contrast CT scan of the chest, abdomen and pelvis was performed, as it was deemed too dangerous to perform a contrast CT in view the risk of contrast nephropathy associated his chronic kidney disease. This showed a 17 cm×14.2 cm

Fig. 2 Bone scan showing high uptake in the right mid-humeral shaft

Fig. 3 Non-contrast CT scan showing 17 cm×14.2 cm mixed attenuating lesion in relation to segment V/VI of the liver; axial view (a), sagittal view (b) and coronal view (c)

J Gastrointest Canc Fig. 4 Acoustic radiation force impulse (ARFI) elastography demonstrating an increased liver mean propagation velocity of 2.99 m/s consistent with liver cirrhosis

oncology team felt it to be in the patient’s best interests not to undergo systemic chemotherapy with sorafenib. He achieved pain relief with the radiotherapy, and he remains alive at 4 months follow-up.

Discussion Our patient’s presentation with pain secondary to an isolated humeral metastases from primary hepatocellular carcinoma is a highly unusual one, and there are only a handful of case reports describing isolated humeral metastases due to HCC [6–8]. Generally, bone metastases tend to affect the axial skeleton, pelvis and ribs, with distant site being rare. Furthermore, they tend to be accompanied by other metastases when found [6]. The spread of hepatocellular carcinoma to bone is generally accepted to be via the haematogenous route [9]. Furthermore, some authors postulate that the most likely method of spread is via the portal vein-vertebral plexuses, thus explaining the increased proportion of skeletal metastases [5]. However, this theory is not supported by the rare findings of isolated distant metastases such as the isolated humeral metastases in the case of our patient. Clear cell carcinoma of the liver is a rare histological subgroup of primary hepatocellular carcinoma (HCC), which is characterised by diffuse clear cells, which show a clear cytoplasm that does not stain with haematoxylin-eosin [10]. A study of 149 cases of HCC showed that clear cell cancer occurs with an incidence of 3.4 % in HCC arising in noncirrhotic livers, while it occurs in 8.8 % of HCC cases on the background of cirrhosis [11]. Clear cell carcinoma of hepatic origin can often be difficult to differentiate from other cancers especially renal cell clear

cancer [12]. Minervini et al. [13] showed that immunochemical staining with HepPar1 alone (a monoclonal antibody highly specific for benign and malignant hepatocytes) had an 82 % sensitivity and 90 % specificity in detecting HCC. In addition, polyclonal antibody to carcinoembryonic antigen with a canalicular pattern had a sensitivity of 79 % and specificity of 97 % for hepatocellular clear cell cancer. The combination of the two immunological tests yielded higher sensitivity and specificity [13]. In the case of our patient, the positive stain for HepPar1 and pCEA (canalicular pattern), in combination with the elevated AFP levels, and the radiological finding of a liver lesion confirmed the diagnosis of clear cell HCC (Fig. 5).

Fig. 5 Bone histology. a Positive pCEA stain (cannicular pattern), b positive HepPar1 stain and c haemotoxylin and eosin stain (×400 magnification)

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Although our patient was not known to have liver disease, he had several risk factors for it. He had long-standing poorly controlled type II diabetes, obesity, hypercholesterolemia and hypertension as well as a history of tobacco smoking, which have all been shown to be risk factors for the development of hepatocellular carcinoma [2]. It is likely that our patient had previously undiagnosed nonalcoholic steatohepatitis leading to his cirrhosis and subsequent HCC development. Metastatic HCC generally confers a poor prognosis, and median survival in patients with isolated bone metastasis is 8 months reference, while patients with additional solid organ metastasis have a median survival period of 3 months. The SHARP trial [14] comparing the effectiveness of sorafenib (a multikinase inhibitor that inhibits tumour blood vessel development and tumour cell proliferation) to placebo found that it prolonged mean survival by 3 months compared to placebo in patients with advanced hepatocellular carcinoma [14]. However, strict patient selection criteria such as the inclusion of patients with a performance status of 0–2 only reflect that our patient may not have benefited from this treatment. Patients with bony metastases secondary to HCC are often symptomatic, and the pain can often be debilitating [15]. In a case series of 57 patients receiving targeted radiotherapy to the affected bone, approximately 84 % achieved adequate pain relief as was the case with our patient [16].

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Conclusion Hepatocellular carcinoma could be considered in the differential diagnosis for patients presenting with pathological fractures. This is particularly valid as the incidence of the silent disease nonalcoholic steatohepatitis (an increasingly recognised risk factor for the development of HCC) is increasing. Hence, it is important to alert physicians to this mode of presentation as it may well become more frequent in the future. Furthermore, immunochemistry assays are an important tool in determining the source of primary tumour.

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Conflict of Interest The authors have no conflict of interest to declare.

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