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Undifferentiated Embryonal Sarcoma of the Liver: A Concise Review.

The term undifferentiated embryonal sarcoma of the liver (UESL) was introduced by Stocker and Ishak (1) in 1978 to describe groups of mesenchymal tumor in the liver that did not show evidence of differentiation. This entity occurs mainly in children between 6 and 10 years of age, without racial/ethnic or sex predominance. It is the third most common primary liver malignancy after hepatoblastoma and hepatocellular carcinoma in this patient population. (1,2) Although rare, UESL has also been reported in adult patients, with a female predominance. (3,4) The oldest reported patient was an 86-year-old woman, described by Ellis and Cotton (5) in 1983. Despite its aggressive nature, UESL is a potentially treatable disease with multimodal management and supportive therapy. (6) Early diagnosis is the key to increase the chances of long-term survival. However, the diagnosis is often challenging because of the overlapping epidemiological, clinical, and radiological findings with those of other liver tumors. (7)


Patients with UESL usually are seen with an abdominal mass with or without abdominal pain. Secondary symptoms such as fever, weight loss, anorexia, vomiting, diarrhea, lethargy, constipation, and respiratory distress can also be seen. (1,6,8) Fever is usually associated with hemorrhage and necrosis identified in the tumor. (9) Spontaneous rupture of the lesion in the abdominal cavity due to its rapid growth has also been reported. (10)

No specific laboratory finding is associated with UESL. Liver test results and neoplastic markers are usually normal in these patients. However, it is not uncommon to see slightly elevated transaminase levels and erythrocyte sedimentation rates, leukocytosis, or leukopenia. (1,9) In addition, rare cases with increased levels of [alpha]-fetoprotein and cancer antigen 125 have been reported. (11,12)

Radiological findings of UESL are also nonspecific. Ultrasonography usually shows a large mass with mixed solid and cystic components. Undifferentiated embryonal sarcoma of the liver is often mistaken for a benign hepatic lesion because of its cystic appearance. This diagnostic pitfall may cause delayed management. Computed tomography often reveals a large hypodense mass with multiple septations. (13) Magnetic resonance imaging is helpful in the surgical planning because it may detect vascular invasion, biliary obstruction, and hilar adenopathy. (9) All patterns of avascular, hypovascular, and hypervascular morphology have been seen on angiography. (13)


Undifferentiated embryonal sarcoma of the liver usually occurs as a single and well-circumscribed lesion grossly. The well-demarcated appearance is created by a fibrous pseudocapsule, which is formed by compressed liver parenchyma. Although they can be found in either lobe or bilateral lobes simultaneously, most lesions are seen in the right lobe of the liver. The tumor is often larger than 10 cm at the time of diagnosis, and it consists of both solid and cystic components. Cut surface reveals a heterogeneous appearance of gray-white, glistening solid tumor alternating with cystic, gelatinous areas. In addition, dark-brown areas of hemorrhage and yellow, softer areas of necrosis are often seen grossly. (1,8)

Microscopically, the pseudocapsule separates the lesion from the surrounding hepatic parenchyma. Cords and clusters of hepatocytes are commonly seen within the pseudocapsule and at the peripheral margin of the lesion. The solid component of UESL appears sarcomatoid (Figure 1) with a myxoid background. The cells are spindle or stellate shaped with inconspicuous nucleoli and ill-defined cell borders. Multinucleated cells and bizarre cells with hyperchromatic nuclei (Figure 2) are often seen between the sarcomatoid cells. Numerous mitotic figures (Figure 3) are easily identified throughout the tumor. Characteristically, eosinophilic globules can be seen in the tumor cell cytoplasm and extracellular matrix. These globules are positive for periodic acid-Schiff (Figure 4) and resistant to diastase digestion. (1)

Most ultrastructural studies of UESL have shown fibroblastic or fibrohistiocytic differentiation. The consistent findings under electron microscope are the dilated rough endoplasmic reticulum cisternae and prominent electrondense bodies. These electron-dense complexes correspond with the hyaline globules seen histologically. (14) Lipoblastic and myogenic differentiations have also been described in a few studies. (4,15) Lipoblastic differentiation is suggested by the cytoplasmic lipid vacuoles on electron microscopy examination and histologic findings of cells resembling lipoblasts. Myogenic differentiation, characterized by bundles of myofilaments, has been reported in a few older patients. (4,15)


Many studies have shown that UESL does not have a specific immunophenotype. The variable expression of histiocytic, muscle, and epithelial markers is suggestive of primitive stem cells as the origin of this lesion. Most cases are positive for vimentin, desmin, CD68, B-cell lymphoma 2, [[alpha].sub.1]-antitrypsin (Figure 5), and CD10 (Figure 6). Glypican 3 (GPC3), known to be a diagnostic marker for hepatoblastoma and hepatocellular carcinoma, has recently been shown to be positive in a subset of UESL. (16) Therefore, GPC3 staining is not a reliable marker to differentiate UESL from hepatoblastoma and hepatocellular carcinoma. Furthermore, hepatocyte paraffin 1, myogenin, CD34, C-kit (CD117), surfactant (PE10), anaplastic lymphoma kinase 1 (ALK-1), and S100 are negative in most cases. (7,9)

Individual markers are often not helpful in differentiating UESL from other liver tumors. Therefore, multiple immunostains are usually performed to help with the diagnosis. In practice, the negative markers are valuable to rule out the differential diagnoses. Hepatoblastoma and hepatocellular carcinoma are commonly positive for hepatocyte paraffin 1 antibody. Myogenin is usually positive in embryonal rhabdomyosarcoma. CD34 positivity is seen in solitary fibrous tumor and vascular neoplasms. Gastrointestinal stromal tumor is positive for both C-kit and CD34. Nuclear positive staining of C-kit in several UESL cases has been described by Kiani et al. (7) It is important to differentiate this finding from the cytoplasmic staining of C-kit in gastrointestinal stromal tumor. ALK-1 is positive in anaplastic large cell lymphoma and inflammatory pseudotumor. Finally, negative staining for S100 and melanin markers is helpful to exclude melanoma and neural tumors. (7)

The extensive panels of immunohistochemical markers are helpful in diagnosing UESL. However, the antibody selection has to be based on demographic information, clinical history, and histologic findings. Because of the nonspecific immunophenotype, we recommend at least 2 or 3 commonly positive antibodies to confirm the diagnosis of UESL, in addition to markers that are needed to rule out the differential diagnoses.


The concept of mesenchymal origin in UESL is generally accepted, despite its evidently obscure histogenesis. Several groups, including in early publications by Stocker and Ishak, (1,24) have raised the possibility of linkage between UESL and mesenchymal hamartoma (MH). Undifferentiated embryonal sarcoma of the liver is often considered a malignant evolution of MH. (1,17,18) Lauwers et al (18) demonstrated the alteration of chromosome 19 in a UESL case that was arising in an MH. This finding suggested an association between these entities because translocation involving the long arm of chromosome 19 (19q13.4) had been reported in 2 previous MH cases. (19-21)


Undifferentiated embryonal sarcoma of the liver has an exhaustive differential diagnosis list. Patient age is often helpful in narrowing down the differential diagnoses because each hepatic lesion occurs in a distinctive age group. The main differential diagnoses for UESL in the pediatric population are MH, hepatoblastoma, and embryonal rhabdosarcoma of the biliary tree. Variants of hepatocellular carcinoma, gastrointestinal stromal tumor, angiolipoma, leiomyosarcoma, liposarcoma, angiosarcoma, epithelioid hemangioendothelioma, and malignant melanoma are more commonly seen in adults. The differential diagnoses are summarized in the Table.

Hepatoblastoma is the most common malignant hepatic tumor in children. A large study (22) by a pediatric oncology group reported that the mean age at diagnosis is 19 months. As an embryonic tumor of the liver, its histologic features may resemble various stages of liver development. Distinguishing UESL from hepatoblastoma is usually not difficult on the basis of its characteristic histologic appearance and immunophenotype. (1,23)

Mesenchymal hamartoma is the second most common benign hepatic tumor in the pediatric population after infantile hemangioma. It usually manifests in children younger than 2 years, with a male predominance. Histologically, this lesion has both epithelial and stromal components. The epithelial component consists of clustered hepatocytes and elongated, branched bile ducts. The stromal component consists of fibroblasts, inflammatory cells, and small vessels. Often, MH and UESL are considered entities of the same spectrum of diseases because both lesions share the same cytogenetic abnormality. (19,24)

Embryonal rhabdomyosarcoma of the biliary tree is usually seen in patients younger than 5 years. Its distinct clinical presentations are suggestive of viral hepatitis or obstructive jaundice. These clinical symptoms of fever and icteric are important in differentiating it from UESL. The tumor shows a botryoid growth pattern into the lumen of the bile duct. Moreover, compact layers of neoplastic cells (cambium layer) with abundant mitoses are seen histologically underneath the biliary epithelium. (1) Skeletal muscle markers such as myogenin and myogenin differentiation 1 are usually positive in this lesion. (25)

Variants of hepatocellular carcinoma such as scirrhous type and those with sarcomatoid features are sometimes difficult to distinguish from UESL. Intracellular bile, nests of polygonal cells, and Mallory hyaline bodies are the diagnostic clues of hepatocellular carcinoma. Moreover, positivity for hepatocyte paraffin 1 stain is helpful in ruling out UESL. (26)

Gastrointestinal stromal tumor in the liver consists of spindle-shaped epithelioid cells with eosinophilic fibrillary cytoplasm. Positive staining with C-kit or CD34 is important for diagnostic confirmation and is a predictor of successful therapy with tyrosine kinase inhibitor. (26)

Angiomyolipoma, which is considered a perivascular epithelioid cell tumor, is characterized by the presence of blood vessels, smooth muscle cells, and adipose cells histologically. It may be misdiagnosed as sarcoma when it manifests with pleomorphic spindle cells. This lesion is characteristically positive for HMB-45 and other melanocytic markers. (4,26)

High-grade sarcomas, including leiomyosarcoma, liposarcoma, and angiosarcoma, are also important entities that should be distinguished from UESL. Although each entity can exhibit pleomorphic epithelioid and spindle cells, immunohistochemistry is a reliable method to diagnose these entities. Typical markers of leiomyosarcoma are smooth muscle actin, desmin, myosin, and H-caldesmon. Murine double minute 2 is positive in liposarcoma, and vascular markers (CD31, CD34, and factor VIII) are positive in angiosarcoma. (26)

Epithelioid hemangioendothelioma is a rare, lower-grade vascular tumor in adults, with a female predominance. Histologically, the tumor is composed of epithelioid cells with characteristic intracytoplasmic vacuoles. The myxoid background often creates a histologic appearance similar to that of UESL. Endothelial marker-positive tumor cells are helpful in diagnosing this variant of vascular tumor. (26)

The histologic appearance of malignant melanoma in the liver may sometimes resemble UESL. Pertinent clinical history, the presence of melanin pigments, and melanocytic markers are helpful tools in diagnosing malignant melanoma. (26)


In the past, prognosis of UESL had been poor. In 1990, Leuschner et al (27) reported a low survival rate (37%) of patients with UESL. At that time, management of UESL relied primarily on surgical resection. However, the prog nosis has slowly improved as these patients are managed with multimodal treatment, including radiation therapy and chemotherapy. (6)

Neoadjuvant chemotherapy is often helpful in unresectable cases. In addition, postoperative chemotherapy and radiation therapy are often reasonable options, particularly in surgical cases with positive margins. Bisogno et al (6) reported the success of an alkylating-based regimen with or without anthracyclines in treating UESL. May et al (28) recently reported the successful outcome of patients with UESL who received a vincristine, actinomycin-D, and cyclophosphamide regimen, which was initially developed for patients with intermediate-risk rhabdomyosarcoma. Orthotopic liver transplantation has been reported as a successful management for patients with recurrent and refractory disease. (29) Furthermore, 18-fluorodeoxyglucose positron emission tomography has been useful in evaluating the response after chemotherapy. (29)

Studies (6,28-30) have shown improved survival rates, ranging from 70% to 100%, in patients who were treated with multimodal therapy. The recurrence rate in UESL is higher during the first 2 years after surgery, and the risk is higher with positive resection margins and cases with spontaneous or iatrogenic rupture of the hepatic lesion. (6)


In conclusion, although UESL is predominantly seen in children, the lesion can occur at any age. Because its clinical and radiological findings are often not specific, the diagnosis of UESL relies on histologic examination and immunohistochemical evaluation. The multimodal treatment necessitates concise and timely diagnosis to improve the survival rate.

Please Note: Illustration(s) are not available due to copyright restrictions.


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Juan Putra, MD; Kim Ornvold, MD

Accepted for publication November 20, 2013.

From the Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Juan Putra, MD, Department of Pathology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (e-mail:

Caption: Figure 1. Sarcomatoid component of undifferentiated embryonal sarcoma of the liver with a myxoid background (hematoxylin-eosin, original magnification X200).

Caption: Figure 2. Pleomorphic cells with numerous hyperchromatic nuclei (hematoxylin-eosin, original magnification X400).

Caption: Figure 3. Numerous mitotic figures are seen in undifferentiated embryonal sarcoma of the liver (hematoxylin-eosin, original magnification X400).

Caption: Figure 4. Intracytoplasmic globules in the center of the photomicrograph are positive for periodic acid-Schiff stain (original magnification X400).

Caption: Figure 5. Tumor cells are strongly positive for [[alpha].sub.1]-antitrypsin (original magnification X400).

Caption: Figure 6. Strong membranous staining of tumor cells with CDJ0 (original magnification X400).
Differential Diagnoses of Undifferentiated Embryonal Sarcoma of the
Liver (UESL)

Diagnosis               Demographics        Clinical History

UESL                    M = F, age 6-10 y   Abdominal mass, pain;
                                            fever; other
                                            constitutional symptoms

Hepatoblastoma          M to F ratio 3:2,   Enlarged abdominal mass,
                        mean age 19 mo      constitutional symptoms,
                                            thrombocytosis, elevated
                                            [alpha]-fetoprotein level

Mesenchymal hamartoma   M > F, age <2 y     Enlarged liver mass,
                                            respiratory distress due
                                            to tumor compression

Embryonal               F > M, age <5 y     Fever, icteric
rhabdomyosarcoma of
the biliary tree

Hepatocellular          M = F, adults       Abdominal mass,
carcinoma                                   constitutional symptoms

Gastrointestinal        M = F, adults       Intra-abdominal mass
stromal tumor

Angiomyolipoma          F > M, adults       Intra-abdominal mass

High-grade sarcomas

(1) Leiomyosarcoma      (1) M = F, adults   Intra-abdominal mass

(2) Liposarcoma         (2) M > F, adults

(3) Angiosarcoma        (3) M > F, adults

Epithelioid             F > M, adults       Intra-abdominal mass,
hemangioendothelioma                        abdominal pain,
                                            jaundice, constitutional

Malignant melanoma in   M = F, adults       Primary or metastatic
the liver                                   tumor nodules with
                                            nonspecific symptoms

Diagnosis               Histologic Features

UESL                    Sarcomatoid, high-grade
                        tumor cells with myxoid
                        background, high mitotic
                        activity, characteristic
                        eosinophilic globules

Hepatoblastoma          Different subtypes
                        resemble various stages
                        of liver development

Mesenchymal hamartoma   Clustered hepatocytes;
                        elongated, branched bile
                        ducts with stromal
                        component (fibroblasts,

Embryonal               Cambium layer of small
rhabdomyosarcoma of     blue tumor cells
the biliary tree        underneath the biliary

Hepatocellular          Intracellular bile, polygonal
carcinoma               cells, Mallory hyaline

Gastrointestinal        Spindle cells with
stromal tumor           eosinophilic fibrillary

Angiomyolipoma          Histologic presence of
                        blood vessels, smooth
                        muscle cells, adipose

High-grade sarcomas

(1) Leiomyosarcoma      High-grade sarcoma with
                        origin cell differentiation
                        (smooth muscle,
                        adipocytes, blood
(2) Liposarcoma         vessels)

(3) Angiosarcoma

Epithelioid             Epithelioid cells with
hemangioendothelioma    intracytoplasmic
                        vacuoles, myxoid

Malignant melanoma in   High-grade polygonal or
the liver               spindle cells with high
                        mitotic activity, melanin
                        pigments are sometimes

Diagnosis               Immunohistochemistry

UESL                    Vimentin, desmin, CD-
                        68, B-cell lymphoma
                        2, [[alpha].sub.1]-antitrypsin,
                        CD10, GPC3

Hepatoblastoma          [beta]-Catenin, Hep Par 1
                        (variable in different
                        subtypes), GPC3

Mesenchymal hamartoma   Hep Par 1, AFP, GPC3,
                        cytokeratins 7 and 19

Embryonal               Myogenin, myogenin
rhabdomyosarcoma of     differentiation 1
the biliary tree

Hepatocellular          Hep Par 1, GPC3, AFP

Gastrointestinal        C-kit (CD117), CD34
stromal tumor

Angiomyolipoma          HMB-45, other
                        melanocytic markers

High-grade sarcomas

(1) Leiomyosarcoma      (1) Smooth muscle actin,
                        desmin, myosin, H-

(2) Liposarcoma         (2) Murine double
                        minute 2

(3) Angiosarcoma        (3) Factor VIII, CD31,

Epithelioid             Factor VIII, CD31, CD34

Malignant melanoma in   Melanocytic markers,
the liver               including HMB-45,
                        antigen recognized by
                        T cells, melan-A, S100

Abbreviations. F, female; GPC3, glypican 3; Hep Par 1, hepatocyte
paraffin 1; M, male.
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Author:Putra, Juan; Ornvold, Kim
Publication:Archives of Pathology & Laboratory Medicine
Date:Feb 1, 2015
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