Primary hepatic angiosarcoma misdiagnosed as hemangioma despite repeated negative biopsies and sclerotherapy: A diagnostic pitfall

Abstract

Primary hepatic angiosarcoma is a very rare vascular malignancy with highly variable imaging and pathologic appearances, occasionally resembling a benign hemangioma. We describe a 62-year-old woman who presented with profound anemia and severe thrombocytopenia and multifocal hepatic lesions repeatedly interpreted as hemangioma on core needle biopsies. She underwent 1 sessions of sclerotherapy. With rapid interval enlargement and atypical MRI features, a repeat biopsy established the diagnosis of hepatic angiosarcoma, supported by immunohistochemistry. Her course was complicated by acute kidney injury requiring hemodialysis; she subsequently suffered 2 cardiac arrests 1 day apart and finally died despite resuscitation. This case underscores the need to revisit the diagnosis when a presumed hemangioma shows progressive growth, atypical enhancement patterns, or discordant clinical behavior.

Introduction

Primary hepatic angiosarcoma is a very rare malignant tumor that arises from vascular endothelial cells, accounting for less than 2% of primary hepatic malignancies. It is characterized by an aggressive clinical course, early metastasis, and a poor prognosis. Clinical and imaging findings are often nonspecific, and the diagnosis is frequently delayed or missed.

Its radiologic features span a wide spectrum and may overlap with benign vascular lesions, particularly when tumors are large, hemorrhagic, or multifocal. In addition, a biopsy may be nondiagnostic because of necrosis, hemorrhage, or sampling of nonrepresentative tissue.

We presented a case initially managed as a hemangioma with Kasabach–Merritt syndrome for several months, in which malignancy was recognized only after progression and repeat tissue sampling, highlighting the diagnostic pitfalls and the importance of maintaining suspicion for angiosarcoma in atypical vascular liver lesions.

Case presentation

A 62-year-old woman initially presented with right upper quadrant (RUQ) discomfort. Ultrasound examination revealed multiple hepatic lesions that were considered most consistent with hemangiomas. At the outside center, an ultrasound-guided core needle biopsy was performed to confirm the diagnosis, and the results were reported as hemangioma. She had no history of chronic liver disease, alcohol use, viral hepatitis, or prior malignancy.

The patient was subsequently followed with periodic ultrasound examinations for approximately 3 months. During this period, she experienced worsening abdominal discomfort, and interval growth of the hepatic lesions was noted on follow-up imaging. As a result, she underwent a session of sclerotherapy for symptomatic relief (Fig. 1). Approximately 2 months after sclerotherapy, the patient developed further worsening pain accompanied by marked unintentional weight loss. Examination revealed hepatomegaly without jaundice or ascites. A repeat biopsy was performed at that time, which again was interpreted as hemangioma. With continued clinical deterioration 2 weeks after the second biopsy, she was referred to and hospitalized at our institution for further evaluation.

Fig. 1.

After ultrasound-guided access, contrast injection with fluoroscopic surveillance is performed to check the needle tip position prior to sclerotherapy.

Laboratory testing revealed severe bicytopenia, with hemoglobin falling to 5.4 g/dL and platelet count to 27 × 10⁹/L. Also, reticulocytosis was noted with a reticulocyte count of 4.5% suggestive of a compensatory marrow response to anemia. Liver enzymes were elevated. Coagulation testing demonstrated a mildly prolonged International normalized ratio (INR) of 1.35. Serum tumor markers, including AFP, CEA, and CA19-9, were within normal limits.

Because of the combination of anemia and thrombocytopenia, hematologic evaluation was performed. Peripheral blood smear and bone marrow aspiration/biopsy were reported as unremarkable, with no evidence of leukemia or other marrow pathology. These findings raised concern for a consumptive coagulopathy associated with the vascular tumor, although complete coagulation parameters such as fibrinogen and D-dimer levels were unavailable. Occult blood was reportedly detected in stool, and endoscopic assessment was performed due to concern for malignancy; results were reportedly normal. A contrast-enhanced CT scan was obtained, followed by liver MRI for further characterization of the lesions.

Imaging

Triphasic Contrast-enhanced abdominal CT was obtained following administration of iodixanol (Visipaque) at a dose of 2 ml/kg with arterial phase at 40s, portal venous phase at 70s, and delayed phase at 180s. It demonstrated multifocal hepatic hypodense lesions, some of which showed progressive enhancement. Although some larger lesions showed several peripheral enhancing nodules resembling hemangioma, there was no typical progressive centripetal fill-in on delayed imaging (Fig. 2).

Fig. 2.

Contrast-enhanced abdominal CT: arterial (A), portal (B) & delayed phase (C); demonstrating multifocal hepatic lesions, including a dominant right hepatic lobe mass with several peripheral enhancing nodules resembling hemangioma (straight arrow).

Liver MRI including axial and coronal T2 weighted, and axial heavily T2 weighted images, in phase and opposed phase T1 weighted sequences, Diffusion-weighted imaging (DWI) obtained using b-values of 50 and 800 s/mm², and dynamic post contrast images; was performed following intravenous administration of gadoterate meglumine (Dotarem), an extracellular gadolinium-based contrast agent, at a dose of 0.2 mL/kg. Dynamic postcontrast images were acquired every 20 seconds for the first 2 minutes (at 20, 40, 60, 80, 100, and 120 seconds), followed by a delayed phase at 10 minutes. It showed innumerable lesions involving both hepatic lobes. In the right lobe, confluent lesions formed a large mass measuring approximately 177 × 130 mm (axial) with a craniocaudal extent of about 165 mm, resulting in marked hepatomegaly. Lesions in the left lobe measured approximately 8-25 mm, and essentially no tumor-free hepatic segment was identified. The lesions lacked the expected bright homogenous T2 signal typical of hemangioma and instead showed multiple foci of intrinsic T1 hyperintensity compatible with intralesional hemorrhage (Fig. 3).

Fig. 3.

MRI sequences: T2WI FS (A), T1WI opposed-phase (B) & T1WI in-phase (C) showing high T1WI/low T2WI foci consistent with hemorrhagic changes (straight arrow). DWI with low b-value (D), DWI with high b-value (E), and ADC map (F) demonstrating regions of diffusion restriction with increased signal in DWI and relatively low signal in ADC map in comparison to background liver inconsistent with T2 shine-through commonly seen in hemangioma (curved arrow).

Following contrast administration, variable enhancement patterns were present. Some larger lesions showed several enhancing nodular components peripherally, demonstrating blood-pool–type hyperenhancement. Enhancement was heterogeneous across lesions and many lesions became more conspicuous relative to the background liver on delayed images. Some other smaller lesions revealed diffuse hyperenhancement since arterial phase (Fig. 4). Diffusion-weighted imaging demonstrated only mild hyperintensity with corresponding isointense ADC values, which does not represent true restricted diffusion and was not considered a reliable discriminator from hemangioma. (Fig. 3).

Fig. 4.

Dynamic MRI: arterial phase (A, B & C) in different axial planes showing multiple arterial hyperenhancing lesions with variable appearances (solid arrow) and 1 hypoenhancing lesion with peripheral nodular foci of enhancement (hollow arrow). Arterial (D)، portal (E) & delayed (F) phase showing a large hepatic mass with progressive enhancement resembling hemangioma.

No focal splenic lesions were identified. Limited thoracic coverage showed 2 to 3 small pulmonary nodules considered suspicious for metastases. Despite the biopsy results being suggestive of hemangioma, multifocality, hemorrhagic components, and atypical enhancement patterns, it raised a strong suspicion for a malignant vascular tumor rather than hemangioma. Angiosarcoma was favored in the differential diagnosis, followed by metastatic melanoma or neuroendocrine tumor. Because the imaging findings and clinical coarse were not compatible with a benign hemangioma, another core needle biopsy was performed during hospitalization.

Histopathology

A repeat core needle biopsy from the liver mass was performed after radiologic and clinical progression raised concern for malignancy. The prior outside biopsy material, initially interpreted as hemangioma, was not available for review. Microscopy of the new specimen showed a malignant vascular neoplasm composed of atypical cells with elongated nuclei and scattered vacuolated cytoplasm, with mild cytologic atypia and foci of necrosis (Fig. 5). The initial benign diagnosis can be explained by sampling of nonrepresentative areas, such as bland vascular spaces, hemorrhagic regions, or necrotic tissue, which are well-recognized pitfalls in the biopsy evaluation of hepatic vascular lesions, particularly angiosarcoma.

Fig. 5.

(A) Microscopic examination shows a neoplasm composed of cells with oval to elongated nuclei, mild atypia, and eosinophilic cytoplasm, forming empty spaces marked by an arrow. (B) Necrosis is depicted by an arrow.

Immunohistochemistry demonstrated tumor cell positivity for ERG, a highly sensitive and specific endothelial marker, and focal positivity for smooth muscle actin (SMA). The Ki-67 proliferation index was approximately 50%. The tumor was negative for SOX10, HMB45, Melan-A, cytokeratin (CK), desmin, and HepPar-1. Although additional endothelial markers such as CD31, CD34, and factor VIII–related antigen are commonly used in the evaluation of vascular tumors, ERG expression in this context strongly supported endothelial differentiation. SMA positivity is recognized as a nonspecific finding in angiosarcoma, often reflecting perivascular or myofibroblastic stromal reaction rather than true tumor cell lineage. Taken together with the histologic features, the immunophenotypic profile supported the diagnosis of primary hepatic angiosarcoma.

Clinical course and outcome

During hospitalization, the patient developed acute kidney injury with rising serum creatinine, requiring hemodialysis. Her condition worsened, and she experienced 2 episodes of cardiac arrest approximately 1 day apart. Despite resuscitative measures, she died.

Discussion

Primary hepatic angiosarcoma (PHA) is an exceptionally rare malignant vascular tumor and remains one of the most aggressive primary neoplasms of the liver with a dismal prognosis. Epidemiologically, PHA is estimated to account for ∼2% of primary hepatic neoplasms [1] and has an estimated incidence of ∼0.5-2.5 cases per 10 million population [2]. In available systematic reviews, pooled analyses, and large database studies, most patients present with multifocal or advanced disease, and survival is commonly reported in months even when treatment is pursued [[2], [3], [4]]. Symptoms are often nonspecific and overlap with many benign and malignant hepatic processes. Abdominal discomfort or fullness, hepatomegaly, fatigue, and weight loss are frequent, and cytopenias such as anemia and thrombocytopenia may be prominent [[1], [2], [3], [4]]. In our patient, the combination of progressive symptoms, marked weight loss, severe cytopenias, and rapid interval growth of hepatic lesions ultimately made the original “benign hemangioma” diagnosis difficult to sustain. Importantly, PHA can also present with severe complications including acute liver failure (from extensive parenchymal replacement and/or vascular occlusion) and tumor rupture with hemoperitoneum [1], both of which should heighten suspicion when clinical deterioration is disproportionate to a presumed benign lesion.

From a broader perspective, angiosarcoma involving the liver may be primary or metastatic; robust population-level estimates directly comparing the proportion of primary versus metastatic hepatic angiosarcoma are limited in the literature, but clinicopathologic reviews emphasize that primary hepatic disease is distinctly rare and that metastatic disease must always be excluded clinically and radiologically [1,5]. Among metastatic sources, splenic angiosarcoma is a well-recognized contributor to hepatic metastases; reported overall metastasis rates for splenic angiosarcoma range from 69% to 100%, and the liver is a frequent metastatic site [6]. In practice, metastatic hepatic angiosarcoma typically reflects disseminated disease with rapid clinical decline, whereas the small subset of primary hepatic cases detected before widespread dissemination may be eligible for resection—one of the few interventions associated with any meaningful survival extension [[2], [4]].

Radiologically, one of the challenges is that PHA does not follow a single pattern. It may present as a dominant mass with satellite nodules, multifocal nodules, or diffuse infiltrative disease, and hemorrhage/necrosis are common—features that can make both CT and MRI appearances strikingly heterogeneous [1,7,8]. In our case, intralesional hemorrhage suggested by intrinsic T1 hyperintensity, together with heterogeneous enhancement behavior and increasing lesion conspicuity on delayed phases, supported a malignant vascular process rather than a stable benign vascular lesion [7,8].

Hemangioma is the most frequent alternative diagnosis, especially early in the course or when sampling is limited. A typical cavernous hemangioma shows discontinuous peripheral nodular enhancement with progressive centripetal fill-in and tends to remain stable over time [9]. When a lesion labeled as “hemangioma” demonstrates rapid interval enlargement, multifocal/diffuse involvement, hemorrhagic components, or highly heterogeneous enhancement that does not behave as expected, angiosarcoma should be reconsidered [[7], [8], [9]]. A particularly important pitfall is that angiosarcoma may also demonstrate nodular peripheral (hemangioma-like) enhancement; however, it often lacks the classic “typical hemangioma” MRI signal behavior (eg, uniform very high T2 signal and predictable progressive fill-in), instead showing more heterogeneous T1/T2 signal related to hemorrhage, necrosis, and variable vascular spaces [[7], [8], [9]]. Hypervascular metastases (including melanoma and neuroendocrine tumors) can also look similar in the arterial phase, so clinical context and systematic evaluation remain essential [1,7]. Hepatic epithelioid hemangioendothelioma (EHE) is another key vascular differential diagnosis; although certain imaging tendencies have been described, practical separation from angiosarcoma is not always reliable on imaging alone and requires interpretation in the overall clinical and pathologic context [[10], [11], [12]].

Histopathologic confirmation can be difficult, particularly on core needle biopsy. Hemorrhage and necrosis may dominate the sampled tissue, and viable tumor can be patchy, leading to nondiagnostic or falsely reassuring results—an issue that is well recognized and was clearly reflected by the repeated benign biopsy interpretations in this case [1,13]. Immunohistochemistry is therefore critical to support endothelial differentiation and confirm angiosarcoma, and vascular markers such as ERG can be especially useful [14]. At the same time, distinguishing angiosarcoma from other hepatic vascular tumors (notably hemangioma and EHE) can be challenging because endothelial markers may overlap; thus, diagnosis relies on integrating morphology (infiltrative growth, cytologic atypia, multilayering, necrosis), proliferation index, and clinicoradiologic behavior rather than immunostains alone [1,5,[10], [11], [12],14]. Crucially, immunophenotype cannot reliably determine whether hepatic angiosarcoma is primary or metastatic; correlation with clinical findings and comprehensive imaging evaluation for an extrahepatic primary is mandatory [1,5].

Because PHA is so rare, treatment is not standardized. When disease is localized, surgical resection offers the best chance for prolonged survival, but most patients are not candidates at presentation. Systemic therapy has been used with variable benefit, and locoregional approaches may be considered in selected patients for palliation or control of hemorrhagic complications [[1], [2], [4]]. Overall, this case reinforces a practical point: when clinical evolution and imaging behavior are discordant with a presumed hemangioma, repeat targeted sampling and careful clinicoradiologic correlation are warranted to avoid delayed diagnosis.

Conclusion

Primary hepatic angiosarcoma can mimic hemangioma on imaging and even on initial biopsy. Progressive growth and atypical MRI features should prompt diagnostic re-evaluation. Repeat biopsy with appropriate immunohistochemistry is essential to avoid delayed diagnosis and inappropriate treatment.

Patient consent

Written informed consent for publication of this case report and accompanying images was obtained from the patient's next of kin. A copy of the consent is available for review by the Editor-in-Chief of this journal upon request.