DOI: https://doi.org/10.21203/rs.3.rs-2708435/v1
Sarcomatoid hepatocellular carcinoma (SHC) is rare. As a subtype of hepatocellular carcinoma (HCC), the clinical manifestations of SHC are similar to those of traditional HCC. Surgical resection is the main treatment, and postoperative adjuvant therapy can prolong the life of patients. However, the prognosis of sarcomatoid hepatocellular carcinoma is worse than that traditional HCC.
we report a 69-year-old male patient with sarcomatoid hepatocellular carcinoma who was admitted to the hospital because of liver enlargement. Abdominal computed tomography revealed a mass in the right lobe of the liver (6.8 cm*4.8 cm). After middle hepatectomy, sarcomatous hepatocellular carcinoma was confirmed by histopathology and immunohistochemistry, and the patient was treated with transcatheter arterial chemoembolization(TACE) and targeted drugs after surgery. The patient died 26 months after surgery. Furthermore, we summarized the clinical, pathological, imaging and treatment of this type of tumor to further understand this solid tumor.
Sarcomatoid hepatocellular carcinoma is a rare subtype of hepatocellular carcinoma, Immunohistopathology is the main way to confirm the diagnosis. Due to the high malignancy and recurrence and metastasis rates of SHC, definite pathological diagnosis, suitable postoperative adjuvant therapy and strict follow-up management are helpful to improve the progression-free survival and survival rate of patients with SHC.
Primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of tumor death in China, seriously threatening the life and health of Chinese people.1,2 Globally, liver cancers are the fourth most common cause of cancer-related death and rank sixth in terms of incidence.3 The 5-year survival rate is 18%, making primary liver cancer the second most lethal tumor after pancreatic cancer.4 According to annual projections from the WHO, more than 1 million patients will die from liver cancer in 2030.3 Hepatocellular carcinomas account for approximately 85%-90% of primary liver cancers, and sarcomatoid hepatocellular carcinoma (SHC) is a rare and special subtype of primary hepatocellular carcinoma. It is highly malignant, prone to recurrence and metastasis, insensitive to radiotherapy and chemotherapy, and has a poor long-term prognosis. By analyzing this case and reviewing the previous literature, this study aimed to summarize the clinicopathological features and treatment options of SHC in order to further understand this solid tumor and prolong the life of patients.
This case includes a male patient who was 69 years old. He was admitted to our hospital due to a liver mass that had been progressively increasing for over 4 months without any other clinical symptoms. He had a history of hepatitis B infection for 6 years and took entecavir tablets (5 mg qd), but denied a history of antitumor therapy or steroids. Tumor marker levels were within the normal range: AFP 9.37 ng/ml, CEA 1.91 ng/ml, CA19-9 < 2.00 kU/L, and CA125 29.81 kU/L. Enhanced CT of the upper abdomen showed a massive low-density shadow in the right anterior lobe of the liver, approximately 6.8 cm × 4.6 cm in size, with clear edges and uneven density. Multiple small low-density necrotic areas were seen during the enhanced scan. Obviously uneven enhancement was observed, with a relatively low density in the venous phase and delayed phase (Fig. 1A-D). The clinical diagnosis was primary liver cancer, and hepatectomy was performed in April 2019.
Histopathology showed that the tumor cells were arranged in oval, short fusiform solid sheets, with lymphocytes and blood sinus-like structures in the middle. The cells were clearly shaped, and the different cell phenotypes were clearly visible. Immunohistochemistry revealed the following results: CK 31 (+), CK8 small foci (+), and vimentin (+), and the tumor excision margin was negative (Fig. 2A-D).
Two months after the operation, the patient received TACE combined with
apatinib mesylate tablets (500mg qd). Due to severe headache associated with systolic pressure as high as 220 mmHg, the patient declined adjuvant therapy because of intolerable side effects.
Routine outpatient follow-up was performed every 3–6 months. The lymph nodes between the portal cavity space and para-aortic space were enlarged at the 14th month after the operation (Fig. 3), but the patient refused adjuvant therapy again. The patient remains under follow up. The patient died at the 26th month after operation.
SHC is a rare and complicated malignant neoplasm of the liver; it consists of both malignant epithelial components and atypical spindle cells that express an epithelial phenotype. The proportion of spindle cells ranges from 1–80% but they usually are minor component.5 This article summarizes its clinical, pathological, imaging, treatment based on previous relevant studies, hoping to improve the prognosis, prolong the survival time, and improve the quality of life.
The incidence of SHC is 0.1%-3.9% in all surgically resected HCCs and 3.9–9.4% in HCC autopsies.6–9 As with traditional hepatocellular carcinoma, SHC often occurs in white male patients.10,11 SHC usually has no specific symptoms, and some patients have right upper abdominal pain and fever as the main symptoms. The tumor in our patient was found on routine physical examination. However, the median size of SHC tumors is larger than that of traditional HCC tumors, and most of the tumors are undifferentiated or poorly differentiated.12,13 Compared with traditional hepatocellular carcinoma, SHC is characterized by lower levels of bilirubin, liver enzymes, and AFP and a lower FIB-4 score.13 In this case, all the above indicators were within the normal range. Patients with SHC have worse OS than patients with conventional HCC (1-year OS rate: 20.4% vs 46.7%),12 and the median OS time of patients with SHC is 5.8–12.7 months.10,14
There is higher paracancer involvement and lymph node metastasis in SHC than in traditional HCC.10 In this case, lymph node metastasis appeared on the 14th month after surgery.
The etiology of SHC is unknown, although some anticancer therapies (such as transarterial chemotherapy or chemoembolization, percutaneous ethanol injection therapy, and radiofrequency ablation) have been observed to be associated with SHC.15
The patient in this case had chronic hepatitis B infection without a history of anticancer therapy. Some research suggests that hepatitis B virus infection might be related to SHC.16,17
The pathogenesis of SHC has not been fully elucidated, but it may be related to the following: (1) Dedifferentiation of cancer cells: some poorly differentiated cancer cells lose their original phenotype and differentiate into tumor cells, presenting as spindle-shaped sarcomatoid cells;16 (2) Metaplasia of cancer cells: SHC may represent transformation of an oncogenic component into a sarcomatous component through metaplasia, as there are known mechanisms for transition between cancer and sarcoma;18,19 (3) Dedifferentiation of hepatocellular carcinoma: HCC cells can first transform into pluripotent immature cells and then differentiate into sarcoma.20
SHC is a rare malignancy composed of both carcinomatous and sarcomatous components. The sarcomatoid variant of HCC is characterized histologically by spindle-shaped cells with increased mitotic activity.21
Most SHCs have areas of more typical HCC identified by sufficient sampling, and immunohistochemical staining and clinicopathological factors are also of value in correctly classifying such tumors, especially when the histological material is limited.22
Immunochemistry is of great value in the diagnosis of sarcomatoid hepatocellular carcinoma. Generally, the mesenchymal components of SHC express both mesenchymal and epithelial markers, which is critical for SHC diagnosis. In the present case, the neoplasm primarily consisted of spindle cells with few epithelial components; however, expression of both mesenchymal and epithelial markers of the spindle cells supported a diagnosis of SHC. Vimentin is the most common mesenchymal marker. Other myogenic markers (such as SMA, actin, desmin, and myoglobin), neurogenic markers and osteogenic markers may also be positive in related components.
Sarcomatoid hepatocellular carcinoma is often confused with carcinosarcoma because both tumors have a spindle cell component, and some scholars consider SHC to be the same as carcinosarcoma.23Immunostaining can document lineage differentiation in the sarcomatous component. The spindle cell components of carcinosarcoma are vimentin positive and keratin negative; however, both vimentin and keratin are positive in SHC.24
SHC shows some characteristic changes on CT or magnetic resonance imaging (MRI). Due to the rapid growth of SHC cells, vascular hyperplasia is not present, as the vasculature cannot increase rapidly enough. CT often shows a large low-density shadow with hypovascularity under the capsule, small uneven edges or rotatory enhancement in the arterial phase, as well as central necrosis.25–27Because of the extensive tumor necrosis and vascular invasion, T2-weighted MRI images of the tumor center show fluid-like signal intensity.26,27 Seo reported that most SHCs can be classified as LR-M on MRI by using LI-RADS v2017, but small lesions may be indistinguishable from HCCs.28
However, due to the heterogeneous nature of liver cancer, it is difficult to distinguish SHC from traditional HCC based on imaging findings alone.
The best practices for the management of sarcomatoid hepatocellular carcinoma remain unclear. Hepatectomy is the primary treatment method; however, a very low proportion of patients can have their tumors surgically resected, and R0 resection rates are low 11. Kan reported that after initial surgery, the median OS in the group undergoing subsequent treatment was 8.8 months, and the median OS for the group not undergoing subsequent treatment was 5. 4 months (P < .05). 14In this case, the patient lived for 26 months after surgery, which suggests that early radical surgery and other treatments extend survival for patients with SHC.
In conclusion, SHC is a rare subtype of hepatocellular carcinoma, and sarcomatoid hepatocellular carcinoma and carcinosarcoma are two different pathological entities. The clinical manifestations of SHC are similar to those of traditional hepatocellular carcinoma. Immunohistopathology is the main way to confirm the diagnosis. Due to the high malignancy and recurrence and metastasis rates of SHC, definite pathological diagnosis, suitable postoperative adjuvant therapy and strict follow-up management are helpful to improve the progression-free survival and survival rate of patients with SHC.
SHC：Sarcomatoid hepatocellular carcinoma;
HCC：Hepatocellular carcinoma;
CT：Computed tomography;
MRI：Magnetic Resonance Imaging;
TACE：Transcatheter arterial chemoembolization;
WHO：World Health Organization;
AFP：α-fetoprotein;
CEA：carcinoembryonic antigen;
CA19-9: Carbohydrate antigen 19-9;
CA125: Carbohydrate antigen 125;
CK: Cytokeratin;
SMA：Smooth muscle actin.
Ethics approval and consent to participate
The ethical approval was given by the medical ethics Committee of the First Affiliated Hospital of Chongqing Medical University
Consent for publication
For the publication of this case report, including images from it, informed consent was obtained by telephone from the patient's family.
Availability of data and materials
The data used to support the findings of this study are included within the article.
Competing interests
The authors declare that there are no conflicts of interests regarding the publication of this paper.
Funding
None.
Authors' contributions
Fang Luo and Hang Zhou performed the surgery; Hang Zhou and Xiaorong Chen collected all the data and pictures of the article and made major contributions to the writing of the article; Fang Luo supervised the writing of the article. All authors read and approved the final manuscript.
Acknowledgments
As the authors, we would like to thank our colleagues in radiology and pathology who helped collect article data.