Two cases of primary hepatic osteosarcoma misdiagnosed as hepatocellular carcinoma

Introduction

Extra-skeletal osteosarcoma (ESOS) is a rare malignant mesenchymal tumor characterized by the production of osteoid, bone, or cartilaginous tissue. It primarily occurs in the deep soft tissue of the limbs and retroperitoneum, and rarely occurs in parenchymal organs (1). It accounts for less than 1% of soft tissue sarcomas and 4% of osteosarcomas (2). ESOS predominantly affects elderly patients, with a reported average age of 54 years (3). Hepatic osteosarcoma typically results from the metastatic spread of osteosarcoma originating in the bone. Conversely, primary hepatic osteosarcoma (PHO) is an exceptionally rare condition, with very few cases reported in the literature, the majority of which are individual case reports (4). This article aims to increase the awareness of radiologists regarding this rare disease by presenting two cases of PHO that were initially misdiagnosed as hepatocellular carcinoma (HCC), and to describe the imaging characteristics of the disease.

Case presentation

Case 1

A 65-year-old male patient presented to the hospital with a three-day history of severe upper abdominal pain, which he described as knife-like and disruptive to his nighttime sleep. Laboratory tests revealed elevated levels of alkaline phosphatase (648 U/L), gamma-glutamyltransferase (160 U/L), direct bilirubin (4.8 µmol/L), hypersensitive C-reactive protein (CRP; 13.4 mg/L), and alpha-fetoprotein (AFP; 10.89 ng/mL). The patient’s medical history included hypertension and diabetes, both of which were being managed with medication, and an appendectomy performed some 40 years ago.

Contrast-enhanced abdominal computed tomography (CT) revealed multiple masses of varying sizes in the left lobe of the liver, of which the largest mass was of approximately 170 mm × 120 mm × 130 mm (Figure 1). The largest mass partially extended through the hepatic capsule, and patchy calcifications were observed within it. The solid component of the mass demonstrated hyperattenuation during the arterial phase, followed by wash-out in the portal venous phase, while the necrotic area showed no enhancement. Tumor thrombus was observed in the left branch of the portal vein. Additionally, irregular contours, lobar disproportion, and a widening of the hepatic fissure were observed. A small amount of ascites was also present. The final imaging diagnosis was HCC with portal vein tumor thrombi formation.

Figure 1 Contrast-enhanced abdominal computed tomography (A-E). Multiple masses of varying sizes were observed in the left lobe of the liver, with the largest mass partially extending through the hepatic capsule and exhibiting patchy calcifications (A). The solid component of the mass demonstrated hyperattenuation in the arterial phase, followed by wash-out in the portal venous phase, while the necrotic areas showed no enhancement (B-D). Tumor thrombus was observed in the left branch of the portal vein (E), along with a small amount of ascites. Pathological examination (F) of the radical resection specimen (hematoxylin and eosin, 200×) of the tumor indicated that the tumor cells were short and spindle-shaped, with round or oval nuclei and prominent nucleoli. A mitotic figure was observed, and the tumor cells were diffusely arranged, with varying amounts of bone-like tissue (as indicated by the large arrow) visible in a grid-like pattern. In some areas, osteoclast type multinucleated giant cells (as indicated by the small arrow) were present.

The patient underwent transarterial embolization and hepatic arteriography due to a progressive decrease in the hemoglobin concentration after liver biopsy. Post-embolization arteriography confirmed the occlusion of tumor-supplying arteries of the left liver lobe, and the deposition of iodized oil in the tumor. Subsequently, the patient underwent a left hemihepatectomy due to his strong desire for surgical intervention. Intraoperatively, a huge ruptured and bleeding tumor was identified in the left outer lobe of the liver, which was brittle and invaded the greater curvature of the stomach, greater omentum, duodenum, jejunum, and spleen, with extensive intestinal adhesions. Metastases were also visible in the right lobe of the liver.

Histopathology and immunohistochemistry confirmed a diagnosis of osteosarcoma. The immunohistochemistry results were as follows: CK-pan (AE1/AE3)(−), EMA(−), S-100(−), SMA(−), HMB45(−), CD34 (vascular +), Melan-A(−), CD117(−), DOG1(−), SALL4(−), AFP(−), HCG(−), SATB2(+), SOX10(−), CD99(−), ERG(−), Oct-4(−), MDM2 (partially weak +), P16(−), TLE-1(+), BRG1(+), INI-1(+), TFE3(−), CDK4(−), Caldesmon(−), Calponin(−), BCL-2(−), β-catenin(−), P53 (expression lost), BRAF V600E(−), MLH1(+), LCA(−), and D2-40(−). Special staining revealed reticulin stain (reticular fibers +), and PAS(+). Contrast-enhanced CT performed one week postoperatively suggested multiple metastases in the peritoneum and omentum with gastric wall involvement and ascites.

Case 2

A 64-year-old male patient was admitted to the hospital with a five-day history of nausea, vomiting and heartburn. Laboratory tests indicated elevated levels of aspartate aminotransferase (50 U/L; reference range, 15–40 U/L), lactate dehydrogenase (449 IU/L; reference range, 120–250 IU/L), alkaline phosphatase (1,054 U/L; reference range, 45–125 U/L), gamma-glutamyltransferase (412 U/L; reference range, 10–60 U/L), direct bilirubin (4.9 µmol/L; reference range, 0.0–4.0 µmol/L), hypersensitive CRP (116.0 mg/L; reference range, <6.0 mg/L), carbohydrate antigen 19-9 (1,146.00 U/mL; reference range, <37.00 U/mL), carbohydrate antigen 125 (231.70 U/mL; reference range, <35.00 U/mL), and AFP (1.76 ng/mL).

The patient had no history of hepatitis. Abdominal contrast-enhanced CT (Figure 2) showed a large heterogeneous mass (163 mm × 128 mm × 160 mm) with a blurred boundary and patchy calcifications in the right lobe of the liver. The mass displayed hyper-signal intensity on T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI), and a hypointense signal on T1-weighted imaging (T1WI) with a blurred boundary. The solid component of the mass showed significant enhancement during enhanced scanning, while the necrotic area showed no enhancement. Tumor embolus was detected in the middle hepatic vein and the adjacent hepatic capsule was breached by the tumor.

Figure 2 Abdominal contrast-enhanced CT scans (A-C) and abdominal enhanced MRI scans (D-H). The CT scan showed a large heterogeneous mass with a blurred boundary and patchy calcifications in the right lobe of the liver (A). MRI scans showed hyper-signal intensity on T2WI and DWI (D,E), hypo-signal intensity on T1WI with a blurred boundary (F). The solid component of the mass showed significant enhancement during enhanced scanning, while the necrotic area showed no enhancement (B,C). Tumor embolus was detected in the middle hepatic vein (G,H). The adjacent hepatic capsule was breached by the tumor, with the adjacent omentum exhibiting thickened enhancement and turbid changes (C). Biopsy pathology (hematoxylin and eosin, 200×) (I) indicated oval or spindle-shaped tumor cells with significant pleomorphisms, large, deeply stained nuclei, and an increased nucleocytoplasmic ratio. Some areas showed an eosinophilic osteoid matrix (as indicated by the large arrow), and focal necrosis (as indicated by the small arrow). CT, computed tomography; DWI, diffusion-weighted imaging; MRI, magnetic resonance imaging; T1WI, T1-weighted imaging; T2WI, T2-weighted imaging.

Based on the imaging findings, a preoperative diagnosis of HCC was made. Liver biopsy was subsequently performed, confirming the diagnosis of osteosarcoma. The immunohistochemistry analysis yielded the following results: Hepatocyte(−), Arginase-1(−), GS(−), AFP(−), CEA-R(−), CK7(−), CK19(−), CK-pan (AE1/AE3) (a few +), CK-low (a few +), CK-high(–), SATB2(+), CD34(−), CK18(−), and CK8(−).

All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. The Ethics Committee of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine approved this study (No. 2025-1175) and granted a waiver of written informed consent because this study involved a retrospective analysis of anonymized clinical data from two patients.

Discussion

The pathogenesis of PHO remains unclear (5). It is speculated that various internal and external environmental factors, such as chemotherapy, ischemic stress, trauma, or genetic predisposition, which cause DNA damage or changes, may play a role in its development (6). The relationship between hepatitis and osteosarcoma development is uncertain, as only three of the 12 cases reported to date had hepatitis (1). In our two cases, the patients had no history of cirrhosis or chronic hepatitis B or C infection.

PHO typically presents with an insidious onset and atypical symptoms, such as a gradually enlarging abdominal mass that may be accompanied by pain (7). CT and magnetic resonance imaging (MRI) are the main imaging modalities; however, preoperative diagnosis is challenging. A definitive diagnosis of PHO requires a combination of pathological and immunohistochemical analyses (3), along with the exclusion of osteosarcoma lesions in other parts of the body (8). If PHO is suspected, biopsy and surgery are recommended.

In these two cases, CT imaging showed large tumors with liver capsule breakthrough, necroses, rapid wash-in and wash-out of the solid components and tumor emboli, initially suggested HCC. However, both cases exhibited linear, lace-like or radial calcifications extending from the periphery to the center on CT imaging, which differed significantly from those observed in other liver lesions.

Liver calcifications are observed in a variety of diseases, including cystic lesions, inflammatory lesions and neoplasms. Below, we provide a detailed overview of the conditions associated with liver calcifications.

Cystic lesions

• Echinococcosis (hydatid disease) is characterized by partial calcification of the cyst wall or coarse calcifications in the wall and contents.
• Polycystic liver disease is characterized by an enlarged liver with multiple cysts, predominantly located peripherally. Some of these cysts may exhibit partial or complete calcification, presenting as punctate or ring-like calcifications.

Inflammatory lesions

• Brucellosis is characterized by central calcifications. These lesions typically present as lobulated lesions with heterogeneous enhancement, ring enhancement during the arterial phase, and surrounding edema.
• Chronic abscesses may contain central or peripheral small foci of calcifications.
• Granulomatous diseases often present as isolated small nodular calcifications.

Benign tumors

• Adenomas typically present with multiple, coarse, and amorphous calcifications.
• Cavernous hemangiomas occasionally present with multiple punctate or small patchy coarse calcifications.
• Caroli disease is characterized by multiple punctate calcifications associated with cystic lesions representing cystic and fusiform dilations of the intrahepatic bile ducts.

Malignant tumors

• Cholangiocarcinoma has been reported to present with eccentric calcifications in a few cases, which are often associated with a fibroproliferative response in the central part of the lesion. The calcifications can be solitary or multiple with indistinct shapes.
• HCC presents as isolated small calcifications within the central part of the lesion.
• Fibrolamellar HCC presents with calcifications in 67–68% of cases, and often involves the central scar, which may be punctate, nodular, or stellate.
• Hepatoblastoma presents with calcifications in 20–50% of cases, which typically appear as multiple, punctate, and amorphous calcifications in the central low-density parts, usually related to hemorrhagic areas, necrosis, and fibrosis. The calcifications can be coarse. These tumors primarily occur in children.
• Liver metastases may also present with calcifications, especially those with colorectal and ovarian origins, which present as punctate, sandy, and granular calcifications in the mass. However, they can be easily distinguished through endoscopic procedures, pelvic MRI, ultrasound, and other imaging techniques (9).

According to previous literature, the typical calcifications of PHO are coarse and prominent, and can serve as significant imaging characteristics, and tumor bones (osteoid) can be found in 68% of ESOS cases (3). Similarly, marked calcifications were observed in these two cases. Conversely, calcifications in other liver lesions are relatively rare and tend to be small. The morphology of the tumor bone is diverse, presenting in patterns such as cotton-wool, ivory-like, needle-like, linear, lace-like, or radiating, resembling the osteoid observed in bone osteosarcomas (3). These distinctive calcification patterns may aid in diagnosis (5). These tumors may undergo necrosis, cystic changes, and hemorrhage. On contrast-enhanced scans, the solid components of the tumors exhibit significant enhancement, while the cystic and necrotic areas show no enhancement (3).

In the study by Di et al., immunohistochemical analysis of PHO indicated weakly positive SATB2 expression. SATB2 is a nuclear matrix-associated protein that binds to special AT-rich sequences. Its expression is tissue- and stage-specific, and it is predominantly found in the glandular cells of the lower gastrointestinal tract and the osteoblasts of bone tumors, and can thus serve as a valuable biomarker for differential diagnosis (2). In these two cases, the morphology was consistent with malignant tumors, with the tumor cells producing osteoid interstitium, and no other lesions were found. Therefore, PHO was considered, and positive SATB2 immunohistochemistry was instrumental in supporting the diagnosis.

PHO is an extremely rare malignancy and is often discovered at an advanced stage due to its rapid progression. It is characterized by aggressive invasion, distant metastasis, and a short survival period (6). Due to the paucity of literature and the absence of early imaging in the two cases presented, it is still uncertain whether significant calcifications are present when tumors are smaller. Currently, there are no established effective treatment methods; however, surgical resection, combined with adjuvant radiotherapy and chemotherapy, appears to be the most promising therapeutic approach for this disease (8).

Acknowledgments

None.

Footnote

Funding: This work was supported by Hangzhou Medical and Health Science and Technology Project (No. A20241426).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-948/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. The Ethics Committee of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, approved this study (No. 2025-1175) and granted a waiver of written informed consent because this study involved a retrospective analysis of anonymized clinical data from two patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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