Rare infiltrative primary hepatic angiosarcoma: A case report and review of literature

Abstract

BACKGROUND

The most primary sites of angiosarcoma are the skin, breast gland, and soft tissues. Primary hepatic angiosarcoma (PHA) is a rare malignant tumor of mesothelial tissue originating from the liver. PHA often presents with multiple intrahepatic foci or metastasis at the time of presentation due to its nonspecific clinical presentation and highly aggressive nature. There are no established or effective treatment guidelines for PHA, so early detection and early treatment are of great value for patient survival. Unfortunately, there is a paucity of literature on the imaging features of PHA, making the diagnosis and treatment of this disease a considerable challenge.

CASE SUMMARY

In this case report, we present a 59-year-old man who initially presented with abdominal pain and radiating pain in the right shoulder. Magnetic resonance imaging and positron emission tomography-computed tomography revealed multiple intrahepatic nodules that needed to be differentiated from tumors of vascular epithelial origin and tumors with progressive enhancement features, and signs of tumor metastasis were assessed. The patient was then subjected to contrast-enhanced ultrasonography (CEUS) to further clarify the extent of tumor infiltration and the state of microcirculatory perfusion. The manifestations observed on CEUS were similar to the classical characteristic presentation of hepatocellular carcinoma, called "quick wash-in and quick wash-out". In addition, CEUS showed that the lesion exhibited gradual infiltration and growth along the liver pedicle structures with no invading blood vessels. Finally, based on pathological and immunohistochemical tests and the above imaging manifestations, it was confirmed that the patient had infiltrating PHA, which is a rare pathological type of PHA. The patient underwent transcatheter arterial chemoembolization and chemotherapy. Four months after the onset of symptoms, the follow-up radiological examination revealed poor treatment efficacy and rapid deterioration.

CONCLUSION

This case report complements the imaging modalities of a rare infiltrative PHA, in which CEUS and quantitative analysis are found to offer substantial advantages in characterizing the microcirculatory perfusion of the lesion, providing clinicians with diagnostic information at the earliest opportunity to make a diagnosis and develop a treatment strategy to prolong the patient survival.

Key Words: Primary hepatic angiosarcoma, Dynamic contrast-enhanced ultrasonography, Quantitative analysis, Multimodal imaging, Case report

Core Tip: The proportion of the patients with primary hepatic angiosarcoma (PHA) is low, and infiltrating PHA is extremely rarer. The kind of the patients with infiltrating PHA are highly prone to misdiagnosis and missed diagnosis, which leads to the poor prognosis. The contrast-enhanced ultrasonography (CEUS) pattern of the patient in this case report is different from that of previously reported PHA patients. We analyzed the lesions by dynamic CEUS (DCE-US), and their manifestation mimicked the imaging pattern of hepatocellular carcinoma known as "quick wash-in and quick wash-out". DCE-US may be helpful for the diagnosis of infiltrating PHA.

INTRODUCTION

Primary hepatic angiosarcoma (PHA) is a malignant tumor with an endothelial cell origin that accounts for less than 5% of all angiosarcomas[1,2]. PHA is the most common malignant mesenchymal tumor of the liver. It consists of spindle-shaped or pleomorphic cells that are in continuity with the normal vasculature and grow in place of normal endothelial cells arranged along the lumen-like vascular structures[3]. However, PHA accounts for less than 0.5% of all primary liver tumors[4]. As PHA mostly presents with nonspecific clinical symptoms and is a highly aggressive malignant tumor, most patients are diagnosed late and have a poor prognosis, with a median survival of less than 6 months[5].

Contrast-enhanced computed tomography and contrast-enhanced magnetic resonance imaging (MRI) are commonly used imaging modalities for the effective characterization of focal liver lesions[6,7]. Due to the development of contrast-enhanced ultrasonography (CEUS) and its newly developed contrast agents, CEUS has good application value for monitoring the perfusion status of hepatic foci and hepatic parenchyma around lesions[8]. Dynamic CEUS (DCE-US) is a quantitative imaging modality that objectively quantifies tissue microcirculatory perfusion and assesses the efficacy of anti-angiogenic therapy through the dynamic process of contrast agent wash-in and wash-out[9,10]. To the authors’ knowledge, most reported PHAs are of the focal mass type[11,12]. However, few of these reported case reports have included evaluation with both MRI and CEUS. The imaging manifestations of infiltrative PHA are even more rarely reported.

In response, we described a 59-year-old man with infiltrative PHA, and combined MRI and DCE-US with pathological findings to further elucidate the imaging findings of PHA. We hope that this case report will complement the CEUS and DCE-US manifestations of infiltrative PHA and play an important role in diagnosing PHA and guiding its clinical decision-making through early, noninvasive preoperative imaging.

CASE PRESENTATION

Chief complaints

A 59-year-old man presented with right upper abdominal pain without an apparent cause, which recurred the next day with radiating pain in the right shoulder.

History of present illness

The patient presented with right upper abdominal pain without an apparent cause, which recurred the next day with radiating pain in the right shoulder. The finding of gray-scale ultrasonography at an outside hospital suggested multiple intrahepatic lesions. The patient was admitted to our hospital for further diagnosis and systemic treatment.

History of past illness

The patient denied a history of trauma, surgery, blood transfusion or drug allergy.

Personal and family history

The patient denied a history of diabetes mellitus, hypertension, asthma, tuberculosis or schistosomiasis. The patient also denied a family history of associated malignancies or liver diseases.

Physical examination

There were no abnormalities on physical examination.

Laboratory examinations

Except for a mildly elevated alpha-fetoprotein (AFP) level of 9.94 ng/mL, other tumor markers, such as carcinoembryonic antigen (CEA, 1.23 ng/mL), abnormal thrombospondin (31.43 mAu/mL) and carbohydrate antigen 19-9 (CA19-9, 11.37 U/mL) were within the normal range. Other laboratory results were as follows: White blood cell 8.60 × 10⁹/L, neutrophil percentage 77.9%, hemoglobin 144.0 g/L, platelet 226.0 × 10⁹/L, aspartate aminotransferase/alanine aminotransferase 21/28 U/L, total bilirubin 27.6 μmol/L, albumin 43.1 g/L, and lactate dehydrogenase 261 U/L. According to the results of the serological test of autoimmune hepatitis tissue, the patient was weakly positive for anti-hepatic solute antigen type 1, while the other tests were negative. The hepatitis B surface antibody (+), hepatitis B e antibody (+), hepatitis B core antibody (+), and hepatitis E IgG antibody (+).

Imaging examinations

To characterize the intrahepatic lesions, the patient underwent MRI. Abdominal MRI revealed multiple lamellar nodules in the liver with long T1-weighted signals and long T2-weighted signals (Figure 1A and B). The larger lesion (110 mm × 59 mm) exhibited mixed signals. Diffusion-weighted imaging (DWI) revealed diffusion restriction (Figure 1C). Intrahepatic lesions with abnormal lamellar signals showed heterogeneous progressive enhancement in the arterial, portal venous, and delayed phases, and the lesions did not compress or encroach on the hepatic portal vein (Figure 1D-F). In conclusion, based on the MRI findings, the multiple abnormal intrahepatic lesions described above were differentiated from tumors of vascular epithelial origin and tumors with progressive enhancing features such as epithelioid angiomyolipoma. To clarify the degree of progression, positron emission tomography-computed tomography was performed at our hospital. There was no indication of extrahepatic metastasis, such as bone metastasis.

Figure 1 Magnetic resonance imaging of the patient with primary hepatic angiosarcoma. A: Axial T1-weighted image; B: Axial T2-weighted image; C: Diffusion-weighted imaging (DWI); D: Axial T1-weighted image after 150 s enhancement; E: Axial T1-weighted image after 3-min enhancement; F: Axial T1-weighted image after 6-min enhancement. Multiple lamellar signal shadows in the liver with long T1-weighted signals and long T2-weighted signals are shown. A lesion showing diffusion restriction and a high signal on DWI. The lesions showed progressive enhancement in the delayed phase.

To further elucidate the microcirculation perfusion of intrahepatic lesions, the patient underwent the gray-scale ultrasonography and CEUS with a Philips EPIQ7 (Philips Healthcare, Andover, MA, United States) at our hospital. The gray-scale ultrasonography revealed multiple massive and lamellar hypoechoic lesions in the liver with ill-defined borders and heterogeneous echoes (Figure 2A), one of which measured 9.0 cm × 3.4 cm. A color Doppler flow imaging did not reveal significant blood flow signals in the hypoechoic regions. SonoVue^® (Bracco) was dissolved in 5.0 mL of saline. Then, 2.0 mL of SonoVue contrast agent was injected intravenously for CEUS, and the vein was flushed with 5.0 mL of 0.9% saline via an antecubital vein. The patient was instructed to breathe steadily and shallowly throughout the examination. CEUS revealed the lamellar hypoechoic areas described above with heterogeneous hyperenhancement in the arterial phase along the hepatic pedicle structures, followed by contrast washed-out in the arterial phase (Figure 2B-D). The lesions showed inhomogeneous hypoenhancement in the portal venous phase, with well-defined hepatic pedicle structures visibly penetrating the entire lesion, and no compression or invasion of the hepatic portal vein (Figure 2E). In the delayed phase, the lesion exhibited further washed-out. The intensity of the lesion in the delayed phase was significantly lower than that in the surrounding normal liver parenchyma (Figure 2F).

Figure 2 Gray-scale ultrasound and contrast-enhanced ultrasonography of the patient with primary hepatic angiosarcoma. A: The gray-scale ultrasound image showing a patchy hypoechoic area in the liver with an ill-defined border; B: The manifestation of contrast-enhanced ultrasonography (CEUS) at 11 s of arterial phase; C: The manifestation of CEUS at 15 s of arterial phase; D: The manifestation of CEUS at 26 s of the arterial phase; E: The manifestation of CEUS at 41 s of the portal venous phase; F: The manifestation of CEUS after 120 s of the delayed phase. In the arterial phase, the lamellar hypoechoic area exhibited heterogeneous hyperenhancement along the hepatic pedicle structure, and the contrast agent in this area washed-out mildly and rapidly, with no invasion of the hepatic pedicle structure. In the portal venous phase, the area showed slight hypoenhancement, and well-defined hepatic pedicle structures were visible. In the delayed phase, the enhanced region changed to significant hypoenhancement and was significantly lower than the surrounding normal liver parenchyma.

To further quantify the microcirculatory perfusion within the lesion, the CEUS digital imaging and communications in medicine cine loops were transferred to an offline computer for further analysis with a NovoUltrasound Kit (version 1.5.0, GE Healthcare Shanghai). Quantitative analysis via CEUS revealed that the contrast agent arrival time (CAT) of the lesion was 4.45 s, the rise time (RT) of the lesion was 8.44 s, the time to peak (TTP) was 12.89 s, the peak enhancement (PE) was 2.64×10⁸ a.u, the fall time (FT) was 19.17 s and the mean transit time (mTT) was 13.83 s. The quantitative parameters of the normal hepatic parenchyma were as follows: The CAT, 6.80 s; RT, 26.84 s; TTP, 33.64 s; PE, 5.07 ×10⁸ a.u; FT, 34.08 s; and mTT, 57.50 s (Figure 3).

Figure 3 The time-intensity curve of quantitative analysis after contrast-enhanced ultrasonography of the patient with primary hepatic angiosarcoma. A: Regions of interest of the lesion (orange circle) and surrounding hepatic parenchyma (blue circle) were placed manually; B: The time-intensity curve showed that the contrast agent rapidly washed-in within the lesion and rapidly washed-out.

Further diagnostic work-up

To further clarify the diagnosis, percutaneous liver puncture biopsy was performed after systematic evaluation of the patient, whose vital signs were still stable. The pathologic diagnosis was PHA, and the microscopic main changes were highly differentiated (Figure 4). The immunohistochemical results revealed the following: CD31 (+), CD34 (+), ERG (+), FLI1 (+), SMA (+), Arginase-1 (+), Hepatocyte (+), CK19 (+), Desmin (-), HMB45 (-), Cathepsin K (-), Melan-A (-), S-100 (-), SOX10 (-), Glypican-3 (-), ALK-1A4 (-) and STAT6 (-). Ki-67 LI was approximately 20%.

Figure 4 Hematoxylin-eosin staining of the patient with primary hepatic angiosarcoma. Histologic findings revealed sinusoidal dilatation of blood vessels under the microscope, with dysplastic cells, marked pleomorphism, and pigmented nuclei. A: Magnification, (× 40); B: Magnification, (× 100).

FINAL DIAGNOSIS

The patient was ultimately diagnosed with infiltrative PHA on the basis of radiographic and pathologic features.

TREATMENT

According to the above medical records, the patient was given transcatheter arterial chemoembolization at our Department of Interventional Radiology. Intraoperative contrast showed abnormally stained lamellar areas with uneven density and blurred margins. No obvious abnormal staining was observed in the contrast at the end of embolization. With the consent of the patient and his family, the first cycle of chemotherapy (doxorubicin hydrochloride liposomes 50 mg) and other symptomatic supportive treatments were administered first.

OUTCOME AND FOLLOW-UP

Afterwards, the patient was closely followed up and MRI was performed 4 months after the diagnosis was confirmed. MRI revealed a significant increase in the volume of the lesions from the previous admission (Figure 5A-C). The lesions involved part of the right branch of the portal vein, with significant compression and narrowing of the trunk of the hepatic vein and the hepatic segment of the inferior vena cava (Figure 5D-F). No obvious cancer thrombus or thrombosis was found inside them. In addition, the patient also presented with cachexia, including secondary thrombocytopenia, coagulation disorders, severe anemia, and hepatorenal syndrome. Based on the above MRI findings, it could be seen that the treatment effect was not satisfactory.

Figure 5 Magnetic resonance imaging of the patient with primary hepatic angiosarcoma four months after diagnosis. A: Axial T1-weighted image; B: Axial T2-weighted image; C: Diffusion-weighted imaging; D: Axial T1-weighted image in the portal venous phase; E: Axial T1-weighted image in the delayed phase; F: Coronal T1-weighted image in the delayed phase. A large mass with mixed T1-weighted signals and mixed T2-weighted signals was observed in the right lobe of the liver. Multiple nodules with long T1-weighted signals and long T2-weighted signals were also observed in the liver. The large mass in the right lobe of the liver showed peripheral enhancement with hemorrhage. The giant mass compressed some branches of the right branch of the portal vein and the inferior vena cava. The remaining nodules showed progressive enhancement in the delayed phase.

DISCUSSION

Angiosarcoma accounts for 2%-3% of adult soft tissue sarcomas, most of which involve the skin, breast gland, or soft tissues[1,5]. PHA is even rarer, with only 19 cases of PHA identified in a multicenter study between 2005 and 2022[13]. Approximately one-quarter of patients in a past study in the United States were exposed to certain substances such as vinyl chloride monomer, the contrast agent Thorotrast, arsenic, and androgenic anabolic steroids[14]. However, through a literature search in the PubMed, EMBASE, and Scopus databases, Rojas et al[15] found that fewer than 1% of patients were exposed to these substances. Thus, it is extremely difficult to use a history of exposure as a diagnostic clue for PHA. PHA progresses rapidly, with extrahepatic metastasis occurring in half of patients at the time of discovery, the most common sites of metastasis in PHA are the spleen, lungs and bone[16]. Intrasplenic metastasis are rarer, so it provides favorable diagnostic clues for the diagnosis of PHA[17-19].

Most patients present with nonspecific signs and symptoms, such as abdominal pain, bloating, fever, low back pain and weight loss, and nearly 40% of patients are first exposed to this condition at an emergency department because of acute liver failure or spontaneous tumor rupture resulting in hemorrhagic shock[16,20,21]. There are no specific tumor markers for PHA, and tumor marker levels, such as AFP, CA19-9, CA125, and CEA, are within the normal range in nearly 90% of patients or mildly elevated in a few patients[16,22]. These findings were consistent with those of the patient in this case.

There are no treatment guidelines for PHA. According to Mangla et al[4], the median survival of untreated patients was as short as 1.8 months. The poor prognosis of patients with PHA is mostly due to its aggressive nature and early metastasis, as well as low awareness among physicians, which prevent it from being discovered in time for optimal treatments to be administered[23]. Therefore, it is particularly important to determine the imaging manifestations of PHA to provide a timely diagnosis and a basis for subsequent treatment options. Due to the different pathological and histological compositions of PHA, the imaging manifestations are also heterogeneous. On cross-sectional imaging, PHA has four main morphologic patterns, including a single mass, multiple nodules, a mixed masses and multiple nodules, and a diffuse infiltrative nodule[17,24,25]. What we are describing is an extremely rare infiltrative PHA.

MRI reveals the heterogeneity, hemorrhagic, and vascularity in PHA, and the invasive progression of PHA can be quickly observed during the follow-up period. PHA usually presents as a predominantly inhomogeneous low signal on T1-weighted images, and its internal high signal is mostly suggestive of concomitant hemorrhage; T2-weighted imaging exhibits high signal or fluid-fluid planes, which is also highly suggestive of intratumoral hemorrhage[3,17,25]. Most patients exhibit heterogeneous hyperenhancement in the arterial phase and continuous contrast filling in the portal venous and delayed phases[26,27]. This imaging pattern is similar to that of hepatic hemangioma. So are the MRI findings in this early phase of the patient in the case report. Some patients have also been reported to exhibit centrifugal enhancement, which is referred to as a “reverse hemangioma” sign, or a mixed pattern of centripetal and centrifugal enhancement[28]. In the study by Jiang et al[12], the contrast-enhanced MRI manifestations of all patients (n = 4) with PHA included in their study showed centrifugal enhancement. Besides, PHA can also be differentiated from hepatic hemangioma based on follow-up manifestations of the lesions, such as a sudden increase in size, rapid growth and even rupture and bleeding of the lesion. The hemorrhage and necrosis in the lesions could never filled with contrast agent. The MRI findings in the late phase of the patient in the case report were generally consistent with the above description.

The use of CEUS in the diagnosis of PHA has not been thoroughly investigated but can provide important diagnostic clues. Chi et al[29] analyzed patients with PHA who underwent CEUS and showed enhancement in the arterial, portal vein, and delayed phases, but no continuous enhancement in the center of the lesions, which presented as necrotic like features. They suggested that this was the relatively specific CEUS manifestation of PHA. However, the number of patients who underwent CEUS included in the study by Chi et al[29] was limited (n = 3), and it is difficult to evaluate whether it is a relatively specific CEUS feature. Wang et al[30] also analyzed the CEUS manifestations in 3 patients with PHA, and these manifestations were different from those analyzed by Chi et al[29]. The manifestations in the arterial phase showed peripheral irregular enhancement and poor demarcation from the surrounding hepatic parenchyma, with no enhancement in the center of the lesions. In the delayed phase, the contrast agent faded out, and a black hole sign appeared. They concluded that when vessels within the focal tissue are sinusoidally dilated, the blood flow velocity in central region of tumors is significantly reduced, and areas with no enhancement may also be observed via CEUS. Therefore, the nonenhanced areas on CEUS were not definitely hemorrhagic and necrotic. A recent study included six patients with PHA who underwent CEUS; to our knowledge, this study included the largest number of PHA patients who underwent CEUS. Some solid areas in the lesions of all patients showed hyperenhancement in the arterial phase with subsequent contrast agent washing-out and partial areas of persistent perfusion defects[11]. Thus, the presence of lesions with inhomogeneous hyperenhancement in the arterial phase with partial areas of consistent nonenhancement and subsequent hyper or hypo enhancement is considered as a characteristic CEUS manifestation of PHA.

The CEUS presentation of the patient in this case differed from the typical manifestations of PHA. The RT of this lesion was significantly shorter than that of normal liver parenchyma. The TTP of this lesion was also significantly earlier than that of the surrounding normal liver parenchyma. The pattern in this patient resembled that of hepatocellular carcinoma (HCC), termed "quick wash-in and quick wash-out". With its ill-defined border, diffusely infiltrated encircling hepatic pedicle structure and unique presentation on CEUS, we concluded that normal endothelial cells were replaced by diffuse infiltration of tumor cells along the hilar region and hepatic sinusoidal space, followed by the formation of a haphazard, free-anastomosing system of the vasculature. The contrast agent passed rapidly through the free-anastomosing vascular system[12]. Based on the gray-scale ultrasound and CEUS findings of this patient, it is also necessary to differentiate this tumor from diffuse-type HCC and intrahepatic cholangiocarcinoma (ICC). For diffuse-type HCC, CEUS can reveal rapid wash-in in the arterial phase and rapid wash-out in the portal venous and delayed phases[31,32]. Therefore, it is difficult to distinguish HCC from PHA in the patient in this case. However, patients with HCC often have a history of cirrhosis due to hepatitis B, and tumor markers such as AFP can be significantly elevated. On gray-scale ultrasonography, the tumor is often indistinguishable from the cirrhotic background, and diffuse-type HCC mostly develops portal vein thrombosis as tumor cells infiltrate the portal vein, and portal vein thrombosis can be considered a more characteristic manifestation of diffuse-type HCC[33]. CEUS can sensitively identify contrast agent microbubbles in the microcirculation, and is able to distinguish tumor thrombi from non-tumor thrombi[34]. The infiltrative growth of tumor cells along the bile ducts in ICC, often leads to limited narrowing or even occlusion of the bile ducts; thus, distal bile duct dilatation may occur. ICC on gray-scale ultrasound mostly shows irregular morphology, ill-defined borders, and irregular dilatation of the surrounding bile ducts. CEUS tends to reveal peripheral rim-like hyperenhancement in the arterial phase. A combination of blurred lesion borders, peripheral rim-like hyperenhancement in the arterial phase, and elevated CA19-9 levels is a strong predictor of ICC[9,31,35].

In addition, we observed an inconsistency between the performance of MRI and CEUS in the delayed phase in this patient. The lesions showed persistent enhancement in the delayed phase of MRI, but the contrast agent was rapidly washed-out in the arterial phase of CEUS. Wilson et al[36] suggested four reasons for the inconsistency between CEUS and contrast-enhanced MRI; among these reasons, we believe that contrast diffusion is the cause. Since the ultrasound contrast agent is a pure-blood pool contrast agent that cannot penetrate the vascular endothelium into the tissue interstitium, the contrast changes observed on ultrasound are mainly related to microvascular perfusion within the lesion. Due to its small molecular weight, the MRI contrast agent can penetrate through vascular endothelial cells into the tumor mesenchyme, resulting in the manifestation of sustained enhancement during the delayed phase of contrast-enhanced MRI of the patient in the case report.

Pathology and immunohistochemistry are the gold standard methods for diagnosing PHA, but in the past, it was believed that PHA was composed of multiple vascular channels with a rich blood supply, and that the risk of bleeding was high. However, nearly 80% of patients with PHA do not experience significant bleeding after puncture biopsy[17]. Therefore, percutaneous hepatic mass biopsy can be attempted when the patient's vital signs are stable and patient consent is obtained. Moreover, CEUS can clarify the active sites of PHA to facilitate an accurate puncture biopsy of the active components. CEUS prevents false-negative results due to necrotic material in the puncture biopsy, further improving the chances of a definitive diagnosis.

CONCLUSION

PHA is an extremely rare and rapidly progressive primary hepatic malignancy that is insensitive to radiotherapy and has a short survival, requiring a timely and accurate diagnosis. The diagnostic value of multimodality imaging is particularly important for the early detection of PHA and subsequent clinical decision-making because of the lack of specific clinical manifestations and laboratory findings. To our knowledge, the patient described here is the first case of infiltrative PHA with a detailed description of imaging features and quantitative DCE-US analysis. Our case highlights the rarity of infiltrative PHA, the manifestations of which are significantly different from the known imaging characteristics of PHA, and complements the description of CEUS manifestations and quantitative analysis of infiltrative PHA, providing new perspectives for clinicians.