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A rare histologic subtype of hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma: report of a case

Worldwide, primary liver cancer is the fourth leading cause of cancer mortality. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Sarcomatoid hepatocellular carcinoma (SHC) is a rare subtype of HCC with conventional HCC admixed with areas with sarcomatoid morphology. SHC is an aggressive, rapidly growing tumor with unfavorable prognosis. Pedunculated SHC is an uncommon presentation of SHC. Due to its rarity, much remains unknown about the etiopathogenesis, molecular underpinnings, and treatment of SHC. We present a case of an exophytic SHC arising in a background of cirrhosis in an older adult. A resection was performed, but the patient subsequently developed multiple additional intrahepatic metastatic lesions necessitating further treatment with chemotherapy.

Surgical resection was performed. Intraoperatively, the tumor was found to involve segments 2 and 3 of the liver with attachment via adhesions to the stomach, omentum and pancreas. Grossly, the resection specimen showed a 10 × 8 × 7.5 cm firm, cream-colored, multinodular, variegated mass with areas of necrosis arising in a background of cirrhosis ( Figure 3A). Histologically, the majority of the mass demonstrated high grade malignant spindle cell component with focal areas of hepatocellular differentiation consistent with SHC as seen on the prior diagnostic biopsy ( Figure 3B-C). Carcinoma extended to the parenchymal margin. Small-vessel lymphovascular invasion was identified. A possible satellite tumor nodule identified on gross examination was found on microscopy to be a lymph node involved by carcinoma. The background liver was cirrhotic, but showed no evidence of steatosis or steatohepatitis ( Figure 3D).
Postoperatively, the patient did well, however, 10 weeks thereafter, surveillance abdominal CT scan demonstrated multiple small (0.5 to 2 cm) metastatic lesions in the left lobe of the liver. Additional imaging did not reveal metastatic disease elsewhere. Adjuvant chemotherapy was initiated with gemcitabine and cisplatin.

Discussion
Like conventional HCCs, patients with SHC are predominantly male, with a median age at diagnosis between 58 and 62 years [2][3][4]. Patients most commonly present with right upper quadrant pain [9]. As in our case, clinical diagnosis can be more challenging because serum levels of α-fetoprotein, liver enzymes and bilirubin tend to be lower than is usually encountered in conventional HCC [4]. Imaging findings also tend to be varied and not characteristic of conventional HCC [10]. At the time of diagnosis, imaging commonly shows a high rate of vascular invasion and invasion of adjacent organs [11]. But at least one other study has shown no significant difference in the incidence of radiologically detected major portal vein invasion at the time of diagnosis between SHC and nonsarcomatoid PLCs [4].
Secondary sarcomatous transformation of conventional HCC has long been recognized in patients treated with nonsurgical modalities like transarterial chemoembolization [7], ethanol injection therapy [12] and radiofrequency ablation [13]. But for the most part, there does not seem to be a difference in etiology between de novo SHC and conventional HCC. Liao et al. found no significant differences in demographics, etiologic factors and other baseline characteristics between patients with SHC and matched controls with conventional HCC. In particular, there were no significant differences in the rates of hepatitis B and hepatitis C monoinfection, hepatitis B and C coinfection, non-B-non-C hepatitis, alcoholism, metabolic syndrome and cirrhosis [4]. In up to 22.5% of cases, an underlying etiology was not found [4].
Uncertainty surrounds the histogenesis of SHC and other hepatic mixed epithelial-mesenchymal/sarcomatoid tumors. Some studies have suggested an origin of the sarcomatoid element from the epithelial neoplasm via metaplastic [14,15] or neoplastic [16] transformation. In addition to a common gain of chromosome 6p in both components, the sarcomatoid component has been shown to harbor fewer chromosomal changes than the epithelial component. This has led to the theory that both components originate from a common precursor with greater tumor progression in the epithelial component [17]. Murata et al. identified mutation of the TP53 gene in both the epithelial and sarcomatoid cells of a combined hepatocellular-cholangiocarcinoma with sarcomatoid features [16]. Fayyazi et al. proposed clonal expansion of totipotent stem cells with divergent transformation along both epithelial and mesenchymal pathways [18]. Secondary sarcomatoid change in nonsurgically treated HCC has also given rise to the hypothesis that SHC arises from selection pressure for sarcomatoid clones exerted by treatment by way of chronic cellular injury [19].
Compared with conventional HCC, patients with SHC, as in our case, tend to have tumors of larger size [2][3][4]11,20], more frequent occurrence of tumor necrosis [10,21], more advanced stage [3] and higher grade, with higher rates of positive lymph nodes [11,20]. The conventional HCC component is more often poorly differentiated or undifferentiated [2][3][4]. The sarcomatoid component stains positively for vimentin and cytokeratins [8] and negatively for mesenchymal markers like SMA, caldesmon, desmin, DOG-1 and CD34 [4,22]. But while the epithelial component stains similar to conventional HCC of the same grade, hepatocellular markers like HepPar1 and arginase 1, are negative in the sarcomatoid areas. A positive reaction for vimentin is often seen in the sarcomatoid component, but not in the epithelial component [23]. SHC must be differentiated from primary hepatic sarcoma. The diagnosis of sarcoma is based on a combination of the characteristic morphology and IHC profile, and the absence of epithelial differentiation. The terms SHC and hepatic carcinosarcomas are often used synonymously [17]. However, despite their close morphologic resemblance, a distinction can be made. In carcinosarcoma, the spindle cells are negative for keratin while the converse holds in SHC [24]. SHC should also be distinguished from collision tumors with separate primary foci of HCC and sarcoma. Imaging and thorough sampling on gross examination will reveal independent tumors. The absence of intimate commingling of dissimilar tumors on histology and distinct immunoprofiles in the separate tumors is diagnostic.
Due to the rarity of this neoplasm, there is currently no consensus on the management of SHC. Various treatment modalities and combinations thereof have been utilized, including surgical resection, adjuvant and neoadjuvant systemic therapy (chemotherapy, hormone therapy and immunotherapy), ablation, radiotherapy, thermotherapy [9] and transplantation [3]. In multivariate analysis, chemotherapy has been found to be associated with improved overall survival [3].
Stage-for-stage, patients with SHC have comparatively worse outcomes than patients with conventional HCC. SHC is associated with shorter recurrence-free and overall survival and higher rates of extrahepatic metastasis [4,21]. Liao et al. found estimated 1-, 3-and 5-year overall survival rates of 45, 17.5 and 10.0% for SHC compared with 75.0, 48.1 and 28.1% for conventional HCC [4]. Other studies have shown even worse outcomes. Zakka et al. found SHC with the worst 5-year overall survival (9.6%) of all variants of HCC [3]. Wu et al. found a 5-year overall survival of 5.7% for SHC versus 30.1% for conventional HCC [2]. In the study by Li et al., 1-year overall survival for SHC was 22%, and no patients were alive at 5 years [11]. Median overall survival for treated SHC ranges from 4.7 [3] to 8.8 months [5]; the median survival for untreated disease is 5.4 months [5].
Independent risk factors for overall survival include vascular invasion, nonradical surgical resection [11], untreated disease [5], tumor, node, and metastasis (TNM) stage and local invasion [25]. The more frequent occurrence of positive surgical margins in SHC [11,15] also contributes to poorer outcomes [3]. Due to ease of complete resection, outcomes for pedunculated lesions might be better [26].

Conclusion
SHC is a rare, aggressive variant of hepatocellular carcinoma with rapid tumor growth and disease progression. Thus, this neoplasm portends a poorer prognosis compared with conventional HCC.

Future perspective
The lack of a clear understanding of the etiopathogenesis of SHC highlights the need for further studies using experimental, molecular, ultrastructural, IHC and other techniques. Thus, a multicenter collaborative effort is needed to pool cases for larger clinicopathologic studies of this rare entity. These will be important steps to help bridge the development of more effective therapies for this very aggressive lesion.

Executive summary
• Sarcomatoid hepatocellular carcinoma (SHC) is a rare, aggressive subtype of hepatocellular carcinoma (HCC) with a poor prognosis. • The clinical diagnosis of SHC is challenging because of nonspecific imaging findings, along with lower levels of liver function tests and serum tumor markers than encountered with conventional HCC. • The diagnosis of SHC is made by histopathologic analysis which demonstrates a component of conventional HCC admixed with areas of spindled and pleomorphic sarcomatoid morphology. • By immunohistochemistry, the conventional HCC component stains positive with typical HCC markers including HepPar1 and arginase 1, along with cytokeratins; while the sarcomatoid component is negative for HepPar1 and arginase 1 with positivity for vimentin and cytokeratins. • The etiopathogenesis of SHC remains unsettled with competing metaplastic and neoplastic theories.
• Current therapy relies primarily on complete surgical resection.

Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript. future science group 10.2217/hep-2020-0027