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Hepatocellular carcinoma with uncommon sites of metastasis: a rare case report

Hepatocellular carcinoma (HCC) is a highly malignant tumor, causing both intrahepatic and extrahepatic metastases. The extrahepatic metastasis occurs in one-third of patients with HCC and it is associated with a poor prognosis. The most common sites of extrahepatic metastasis are lung, regional lymph nodes, bone, adrenal glands, and peritoneum/omentum. Detection of such extrahepatic metastasis plays a vital role in the staging and treatment planning of HCC. A 60-year-old man was presented to our centre with loss of apetite, generalised weakness, and weight loss. Abdominal examination revealed a firm lump in the right hypochondrium. CT findings revealed a large well-defined hypodense mass in almost entire right lobe of the liver. A well-defined oval, heterogeneously enhancing soft tissue mass lesions were also noted in both adrenal glands and psoas muscles. For histopathological diagnosis, percutaneous ultrasound-guided truecut biopsy was done from right lobe liver mass confirming well differentiated HCC. In the present case report, we present an extremely rare and unique case of HCC with disseminated skeletal muscle metastasis with concomitant bilateral axillary lymph node metastasis. It is crucial for radiologists to detect such extrahepatic sites of metastasis initially at the time of diagnosis for accurate staging and treatment planning for a better prognosis.


Background
In 2020, liver cancer ranked sixth in incidence (905,677 new cases) and third in mortality (830,180 deaths) globally [1]. Hepatocellular carcinoma (HCC) is the predominant form and accounts for 90% of primary liver cancers. HCC is the most common primary liver malignancy with a high risk of metastasis. HCC hematogenous spread occurs via the lymphatic route or by direct invasion resulting in intrahepatic as well as extrahepatic metastasis [2].
The common sites of extrahepatic HCC metastasis with their frequencies are brain (2%), peritoneum/omentum (11%), adrenal glands (11%), bone (28%), regional lymph nodes (53%), and lung (55%) [3,4]. Clinically, the presence of extrahepatic metastasis is considered as an advanced stage of HCC. Where such patients are not considered for curative treatment but treated with palliative intent as locoregional treatment or systemic chemotherapy. Due to its poor prognosis, the median survival was observed to be less than one year. Hence it is important to determine the presence of metastases at the time of initial HCC diagnosis for initiation of appropriate therapy, to determine the survival and follow-up [5,6].
In the present case report, we described an unusual case of HCC presented with both common as well as uncommon sites of metastasis. Where rare multiple widespread skeletal muscle metastasis with concomitant bilateral adrenal and axillary lymph node metastasis was observed without common metastatic site lung. To the best of our knowledge, literature related to such rare occurrences has not been reported before.

Case presentation
A 60-year-old patient was presented to our centre with loss of apetite, generalised weakness, and weight loss. Patient was non alcoholic. Abdominal examination revealed a firm lump in the right hypochondrium. Routine blood tests, liver function tests, hepatitis viral marker, Serum Alpha Feto Protein (AFP, 1.6 ng/ml), Carcinoembryonic Antigen (CEA, 2.2 ng/ml), and Prostate-Specific Antigen (PSA, 0.5 ng/ml) reports were all found to be within normal range.
Abdominal ultrasound was done, revealing a large heteroechoic mass in the right lobe and similar other lesions in the left lobe of the liver. No ascites were found and visualised portal vein shown normal colour flow.
To acquire additional information, a triple phase contrast enhanced CT (CECT) abdomen and pelvis was done. Where, a large well defined hypodense mass in almost entire right lobe of the liver (segment V/VI/VII/ VIII) measuring approximately 180 × 30 × 170 mm was seen with early arterial phase enhancement and early washout in the venous phase. Involvement of segmental portal vein was also observed. Whereas, rest of the portal vein branches and main portal vein has shown no intraluminal thrombus. Another morphologically similar lesion measuring 57 × 46 mm was noted in segment II with early arterial phase enhancement and early washout in venous phase consistent with intrahepatic metastasis (Fig. 1).
A well-defined oval, heterogeneously enhancing soft tissue mass lesions were noted in both adrenal glands measuring approximately 60 × 35 mm in the right adrenal gland and 45 × 34 mm in the left adrenal gland suggesting bilateral adrenal metastasis ( Fig. 2C and D). Multiple lytic lesions in vertebrae, bilateral ribs, and pelvic bones with largest in right iliac bone associated with soft tissue measuring 50 × 36 mm was noted, suggesting bone metastasis ( Fig. 2A, B, and D). Multiple soft tissue enhancing mass lesions were noted in both psoas muscles ( Fig. 3A), in the anterior abdominal wall involving  (Fig. 5B). In addition, multiple enlarged bilateral axillary lymph nodes were noted, with the largest one measuring approximately 21 × 17 mm in the left axilla suggesting metastatic lymph nodes (Fig. 5A). No significant mediastinal or hilar adenopathy or supraclavicular adenopathy was noted. For histopathological diagnosis, percutaneous ultrasound-guided truecut biopsy was done from right lobe liver mass revealing well-differentiated HCC. Subsequently, percutaneous ultrasound-guided truecut biopsy from right rectus abdominis muscle lesion and fine needle aspiration cytology (FNAC) from left axillary lymph node were histopathologically analyzed confirming metastasis.
After initial diagnostic workup and confirmation of metastatic HCC, immunotherapy treatment was initiated using Injection Durvalumab (1500 mg, 9 cycles). Which was well tolerated by the patient with overall survival of 10 months.

Discussion
In patients with HCC, early diagnosis and familiarity with its metastasis sites can profoundly impact the treatment options and prognosis. Correct risk stratification can help in avoiding unnecessary costs, delays in treatment, or disease related morbidities. The incidence of extrahepatic metastasis of HCC was reported to be about 15-17% [7]. The most common sites of extrahepatic metastasis are lungs, adrenal glands, bones, and regional lymph nodes [4]. Metastasis to skeletal muscle and distant lymph nodes are uncommon. The factors associated with the risk of metastasis are alpha fetoprotein levels (AFP, > 400 µg/ml), vascular invasion, index tumor size (> 5 cm), and multifocal or infiltrative tumours [8].
Uchino et al. [9] conducted a study in 342 patients of HCC with extrahepatic metastasis. Where 28 patients were found to have extrahepatic metastasis on initial presentation and the remaining patients developed it during follow-up. The distribution of the metastasis among those patients was as followed-lung (135, 39.5%), lymph node (117, 34.2%), bone (87, 25.4%), adrenal (30, 8.8%), brain (4, 1.2%), spleen (2, 0.6%), and breast (1, 0.3%). The median survival after diagnosis of extrahepatic metastasis was reported to be 8.1 months. In a retrospective study by Katyal et al. [10], CT findings of 403 patients with HCC were reviewed and 148 patients were found to have extrahepatic metastasis. The most frequent site of metastasis in their patients was also found to be lungs (81, 55%), abdominal lymph nodes (60, 41%), and bones (41, 28%). Both Uchino et al. [9] and Katyal et al. [10] reported adrenal gland metastasis in 8.8% and 11% of patients, respectively. The adrenal gland metastasis was considered as the fourth most frequent site of metastasis after the lungs, lymph nodes, and bone. In our patient also multiple lytic bone metastasis and bilateral adrenal metastasis were also seen. However, the most common site of metastasis-lung was found to be normal without any sign of metastasis.
Other forms of metastasis include muscle and skin metastasis. Which in generally may occur via needle seedling post biopsy or by the surgery itself. But the risk of metastasis through this process was found to be as low as 2.7%. However, this is different from muscle metastasis due to hematogenous spread. Intramuscular HCC is another rare metastasis, where very few reports in the literature have reported its presence in para vertebral muscle [7], right gluteal muscle [11], psoas muscle [12], intercostal muscle [13], left iliacus [14], multiple soft tissues [15], pectineal muscle [16], and chest wall [16]. It was also observed that even after curative surgery (hepatic resection/transplantation) or loco-regional treatment (TACE-TransArterial ChemoEmbolisation or TARE-TransArterial Radioembolisation) [12,16,17]. For primary HCC, high chances of developing extra hepatic metastasis was reported during the follow-up period.
In the present case report, our patient has also shown signs of muscle metastasis. However, its extent was completely different compared to earlier literature. Where a widespread multiple muscle metastasis was found in the abdomen, paravertebral, and arms. The muscle metastasis on triphasic CT scan has also shown an early arterial enhancement without washout in portal venous or venous phase as seen in HCC. Another common site of metastasis is regional abdominal lymph nodes. However, distant lymph node  metastasis can also present with the most common site as mediastinal lymph nodes [16]. In our patient, a very rare enlarged bilateral axillary lymph nodes were detected. Only one case report was found in the literature involving the axillary lymph nodes by metastases from HCC [16]. Possible routes for such metastatic spread to axillary lymph nodes might be through the primary tumor involving the upper part of the right liver lobe (under the bare area of the liver) where it spreads via lymphatic vessels to reach parasternal or mediastinal lymph nodes to the axillary lymph nodes. Another alternate possible route for such metastasis may be from the portal venous system to the umbilical region [18]. Whereas in our patient, bilateral axillary lymph node metastasis was seen without mediastinal lymph node involvement itself. Thus the present case report has the peculiarities as mentioned: 1. It described common sites of metastasis as bone and adrenal glands other than lung, which is the first most frequent site of metastasis. 2. Uncommon sites of metastasis to muscles with widespread multiple muscle involvement, which were not described earlier. 3. Uncommon site of metastasis such as axillary lymph nodes. Which was bilateral and not reported yet in literature.

Conclusions
We report the first case of HCC with bilateral axillary lymph node involvement with widespread muscle metastasis. Though this is a single case, it can raise interest in clinicians performing imaging by helping in to focus and identify the uncommon metastasis sites of HCC for patient's overall well-being and timely treatment. It is crucial for radiologists to detect such extrahepatic sites of metastasis initially at the time of diagnosis for accurate staging and treatment planning, as well as in follow up cases (as post resection or post locoregional therapy) to evaluate for recurrence.