Scapula metastasis as unusual site of extrahepatic spread of hepatocellular carcinoma: A case report

Dear Editor, Hepatocellular carcinoma (HCC) is the leading primary malignancy of the liver. Worldwide, established risk factors for HCC are hepatitis B, hepatitis C, liver cirrhosis, aflatoxin exposure, and alcoholism in more than 90% of cases. Additionally, non-alcoholic fatty liver disease (NAFLD), diabetes mellitus, and obesity have also demonstrated the significant association.[1] HCC generally presents with the multifocal intrahepatic lesions with potential for local invasion, and 5–15% of patients present with extrahepatic spread, with lung metastasis being the most frequent. However, presenting with an extrahepatic lesion as the initial presentation of HCC is relatively rare, especially with bone metastasis which occurs in less than 1% of incident cases. The location with the highest incidence of bone metastasis is vertebral bodies and pelvic bones.[2] We report a rare presentation of HCC, with scapular swelling as the initial presentation, in the absence of commonly associated risk factors. As far as we know, only three cases have been reported globally where the scapular lesion was the initial presentation of the HCC[3-5] highlighting the rarity of this presentation. A 60-year-old man, with no known comorbidities, presented with the complaint of left shoulder pain and swelling for the last 3 months. On clinical examination, 6 × 6 cm an ill-defined diffused hard swelling palpable on the left scapular region, without any skin changes. There were no other clinical symptoms. To evaluate the left shoulder, chest X-ray radiography was conducted which suggested an ill-defined osteolytic lesion in the inferior body of the left scapula. Contrast-enhanced computed tomography (CT) scan of the thorax revealed a large lytic area with associated soft tissue measuring 5.8 × 4.6 cm in the inferior body of the left scapula, along with another lytic area in the posterior shaft of the right sixth rib with extraosseous soft tissue component measuring 3.2 × 2.2 cm. Ultrasound (USG)-guided fine-needle aspiration cytology (FNAC) from the left scapular lesion was suggestive of atypical cells favoring poorly differentiated malignant tumor. The patient underwent 18F-fluorodeoxygenase (FDG)-based positron emission tomography-computed tomography (PET-CT) scan, which revealed a metabolically active FDG avid hypodense lesion noted at segment VI of the liver (measuring 2.8 × 2.3 cm) with multiple abdominal and mediastinal lymph nodes, and lytic lesions with soft tissue component at C6, C7, D9, D10, and L3 vertebrae, left scapula, right 6th–8th ribs, bilateral iliac bones, and right acetabulum, along with mildly FDG avid hypodense lesion with calcification noted in the left lobe of thyroid as well [Figure 1a-d]. In view of the above, differential diagnosis was made of metastatic neoplastic etiology of either thyroid gland, or liver, or carcinoma of unknown origin.Figure 1: 18F-FDG avid fused PET-CT Scan. (a) Sagittal section showing FDG avid lytic lesion with soft tissue component at C6, C7, D9, D10 and L3 vertebra (arrows) and para-aortic lymph node (arrow-head). (b) Axial section showing FDG avid lesion in segment VI of liver (arrow) and periportal lymph node (arrow head). Axial section showing FDG avid lytic lesion with soft tissue component, (c) At right iliac bone (arrow), (d) At right 6th-8th rib (arrow) and left scapula (arrow head)His laboratory workup revealed normal bilirubin (total bilirubin—0.62 mg/dL), with elevated levels of alanine aminotransferase (ALT, 84 U/L), aspartate aminotransferase (AST, 86 U/L), and alkaline phosphatase (ALP, 194 U/L); thyroid function test was within normal limits; and viral markers were negative. Serum tumor markers indicated elevated levels of alpha-fetoprotein (AFP, 7780 ng/mL) and lactate dehydrogenase (LDH, 300 U/L), while other tumor markers, including prostate-specific antigen (PSA, 0.73 ng/mL), carcinoembryonic antigen (CEA, 3.19 ng/mL), carbohydrate antigen 19.9 (CA 19.9, 19.32 ng/mL), and total human chorionic gonadotropin (t HCG, <2 mIU/mL), were within normal limits. Left scapular lesion biopsy showed a tumor comprising papillary areas and solid areas. The tumor cells were large with abundant eosinophilic to granular cytoplasm. Based on histomorphological findings, the possibility of metastasis from thyroid, lung, stomach, kidney, and prostate was considered. On immunohistochemistry (IHC), tumor cells were positive for pan-cytokeratin (PanCK), arginase 1, and glypican 3, while negative for synaptophysin, thyroglobulin, thyroid transcription factor-1 (TTF-1), BRAF V600E, cytokeratin 7 (CK7), cytokeratin 20 (CK20), SALL-4, PAX 8, PSA, and AMACR [Figure 2a-f]. FNAC and biopsy from the thyroid gland were negative for malignancy. The patient was finally diagnosed with metastatic HCC, with good performance status (Eastern Cooperative Oncology Group Performance Status-1 [ECOG PS-1]). The patient was planned for palliative radiotherapy and received 20 Gy in five fractions to the left scapula, and eight Gy single fraction to each C6, C7, and L3 along with bisphosphonates followed by sorafenib-based targeted therapy.Figure 2: Histopathological and IHC studies of left scapula biopsy. (a) Hematoxylin and eosin section (20x amplification) from solid looking area shows prominent arborizing vasculature , large cells with abundant clear to eosinophilic cytoplasm, irregular nuclei with some bizzare nuclear forms being seen (arrow). IHC profile, (b) Positive for Glypican 3, (c) Positive for Arginase, (d) Membranous positivity for PanCK, (e) Negative for Synaptophysin, (f) Negative for ThyroglobulinHCC is the most prevalent primary tumor of the liver, known to arise in the setting of chronic liver disease. Patients with compensated cirrhosis who present with complications, such as ascites, encephalopathy, jaundice, or variceal bleeding, should be suspected to have HCC. The incidence of presenting with the extrahepatic spread at the time of diagnosis is only about 5–15%.[1,3] Metastasis to bones is found in 13–16% of metastatic HCC patients, but debutant skeletal metastasis from HCC is less common compared to other malignancies and is considered a rare primary method of presentation. HCC spreading to the skeletal system via the hematogenous route (pulmonary and systemic) is unique, as bone lesion can become symptomatic before the liver disease. Bone metastases from HCC typically manifest as large soft tissue masses causing bone damage.[3] Only three cases have been reported with the scapular lesion as the initial presentation in patients of unknown HCC status [Table 1]. In this case as well, patient reported with flat bone swelling as the initial symptom without any comorbidity and clinical features of liver stigmata, creating a diagnostic dilemma.Table 1: Cases of scapular metastasis as the initial presentation of hepatocellular carcinoma published in the literatureSerum biomarkers play a crucial role in solving the diagnostic riddles. In cases of HCC, AFP above 400 ng/mL is highly sensitive and specific for HCC, with a 99% specificity rate, and also associated with poor prognosis in terms of poor survival and higher recurrence rates.[6] This case also highlights the significance of serum biomarkers; raised levels of AFP indicated HCC and prompted further investigation through IHC studies, which are specific for HCC. Arginase 1 is an enzyme of the urea cycle, which stains both normal and malignant hepatocytes. It is the most sensitive marker for HCC, even for poorly differentiated HCC with high specificity as well. Glypican 3 positivity was observed in 90% of HCC cases, but negative for normal liver tissue, hepatocellular adenoma, and focal nodular hyperplasia. Together, glypican 3 and arginase 1 can detect 100% of poorly differentiated HCC.[7] We also observed the positivity for both glypican 3 and Arginase 1 IHC markers that led to the final diagnosis of metastatic HCC in this study. Despite well-established risk factors for HCC, 10–15% of tumors develop in patients without any identifiable risk factors, and their etiology remains unknown. With recent healthcare advancements and robust diagnostic intervention, their incidence is also on the rise.[8] In this particular case, despite the absence of known risk factors, a gap was identified when a suspicious single lesion was observed on a PET-CT scan, prompting the measurement of serum tumor biomarkers for the liver. The diagnosis was ultimately confirmed through tissue analysis. The incidence of metastatic HCC in patients without any identifiable risk factors increases which also presents with unusual pattern of spread. Whenever a diagnostic dilemma is present, serum biomarkers and tissue diagnosis play a vital role in determining the diagnosis and guiding appropriate management. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.