—  SHORT COURSE #22  —

Tumors In The Liver - Diagnostic Problems

Case 10 - Epithelioid Hemangioendothelioma

Linda D. Ferrell, M.D.
Wendy L. Frankel, M.D.


Clinical findings:
36 year old woman with one tumor in the right lobe and other small nodules in the left lobe. The tumors had white-tan and firm surfaces.


Case 10 - Figure 1 - Nests of atypical cells embedded in a myxohyaline matrix, low power
Case 10 - Figure 2 - Nests and single atypical round cells with a rare intracytoplasmic vacuole containing erythrocytes, high power

Case 10 - Figure 3 - Atypical cells lining vascular spaces, high power
Case 10 - Figure 4 - CD31 immunoreactivity in the atypical cells and lack of staining in admixed benign bile ducts; Cytokeratin postive bile ducts, high power


Pathologic findings: Nests of atypical cells embedded in a myxohyaline matrix, low power. Nests and single atypical round cells with a rare intracytoplasmic vacuole containing erythrocytes.CD31 immunoreactivity in the atypical cells and lack of staining in admixed benign bile ducts.

Diagnosis- Epithelioid Hemangioendothelioma

Comment - Malignant Mesenchymal Lesions

Epithelioid Hemangioendothelioma

Clinical features. Epithelioid hemangioendothelioma (EHE) is a rare, low-grade malignancy that occurs in adults of any age, but tends to be more common in women. Many lesions are discovered as an incidental finding, but presenting symptoms can include upper abdominal mass or discomfort. Serum alkaline phosphatase levels may be elevated. Liver transplantation can be a reasonable means of treatment in unresectable cases, showing a survival similar to hepatocellular carcinoma of the same stage. Overall, the prognosis is better than that of angiosarcoma, even if excision is incomplete or extrahepatic metastases are present.

Gross findings. EHE is a firm, white to yellow tumor that often has an ill-defined border. The tumor is often multifocal with involvement of both right and left liver lobes. Focal calcification can be present, and cause a somewhat gritty consistency.

Microscopic findings. The cells comprising this tumor can be dendritic or epithelioid in appearance. The former are irregularly-shaped, elongated, or stellate cells with branching processes. The cell cytoplasm may contain a vacuole which represents an intracellular "capillary" luminal space. The epithelioid tumor cells are rounder with more abundant cytoplasm than the dendritic cells. These cells often form small papillations or tufts within thin-walled vascular spaces. Both cell types are surrounded by a myxoid to fibrous stroma. Calcification of the more dense type of stroma may be present. The tumor tends to grow around and leave intact the preexisting structures such as the portal zones and residual hepatocytes or bile ducts can be present within the tumor, especially near the periphery of the lesion. The tumor also has a marked predilection for invading vascular structures such as portal and central veins, which can mimic the histologic appearance of vascular thrombosis. Scattered inflammatory cells such as lymphocytes and neutrophils are often seen.

Special studies. Histologic differentiation of this lesion from adenocarcinoma (including cholangiocarcinoma) or HCC can be problematic on routine staining. However, immunohistochemical staining for the endothelial markers such as CD34, CD31, and/or Factor VIII on the tumor cells will confirm the diagnosis of EHE. Care must be taken, however, not to mistake focal keratin positivity in this tumor due to either entrapped hepatocytes or ducts and possibly also in tumor cells for carcinoma. Another diagnostic problem can be the differentiation of EHE from venous thrombosis/veno-occlusive disease as the tumor growth within large vessels can mimic an organizing thrombus.

Angiosarcoma

Clinical features. Angiosarcoma is a rare primary malignant tumor that usually occurs in middle-aged adults, but has also been noted rarely in children, some in the setting of infantile hemangioendothelioma. Other definitive associations include thorotrast and vinyl chloride exposure, but many of these tumors have no apparent etiologic factor. Presenting signs include hepatomegaly, ascites, jaundice, thrombocytopenia, hemoperitoneum, and liver failure. The mean survival after diagnosis is six months.

Gross findings. Angiosarcomas are often large hemorrhagic tumors with indistinct borders and variable solid or cystic areas, the latter usually containing blood. Satellite nodules can be present.

Microscopic findings. The tumor typically has a mixed pattern of histology, with sinusoidal, solid, papillary, and cavernous types of growth. The sinusoidal pattern is the most distinctive growth pattern in the liver. In this pattern, the endothelial cells line both sides of the hepatic cell plates in a scaffold-like arrangement that dissects the plates, and often results in sinusoidal dilation. The tumor cells lining the cell plates are more numerous, more hyperchromatic, and larger than normal endothelial cells. This sinusoidal pattern is more likely to be noted at the periphery of the tumor, and so may represent an early outgrowth of the tumor, which then later transforms into the solid or papillary forms. The solid pattern may have a fascicular or whorled appearance, or may resemble fibrosarcoma. The papillary pattern consists of nodules of stroma lined by tumor cells that protrude into a lumina. The cavernous pattern consists of large blood-filled spaces, and is commonly seen with any of the other patterns.

Special studies. Endothelial markers such as Factor VIII, CD 31, and CD34 will typically be positive on the tumor cells, but not all tumor cells may stain. FVIII is the most sensitive and specific marker for the tumor.

Kaposi's Sarcoma

Clinical features. Kaposi's sarcoma (KS) most often occurs in the liver in the setting of the acquired immune deficiency syndrome (AIDS) usually only after the tumor is known to be present at other sites.

Gross findings. Most of the findings of KS in the liver are similar to those seen at other sites. The tumor can have a fibrous to hemorrhagic, multifocal appearance, often centering around portal triads.

Microscopic findings. The tumor consists of spindled cell proliferation that forms slit-like spaces or, in larger lesions, a more solid, fibrosarcomatous-like pattern. As at other sites, cellular pleomorphism and mitotic activity are minimal, and extravasation of erythrocytes, hemosiderin deposits, and small eosinophilic globules are typically present. One pattern that is typically seen only in the liver is the growth of the spindled tumor cells into and along the sinusoidal spaces, usually at the periphery of the tumor nodules. This pattern of growth results in dilated channels that contain erythrocytes that replace of the normal sinusoids, findings that have a peliotic appearance. The tumor also tends to surround or infiltrate the portal zone, often leaving the hepatic artery and interlobular bile duct intact.

Special studies. The tumor cells are positive for endothelial markers including CD31 and CD34, which can be useful to help differentiate KS from fibroblastic proliferations.

Benign Mesenchymal Lesions

Hemangioma

Clinical features. Hemangioma is the most common primary tumor of the liver. This benign vascular neoplasm is usually noted as an incidental findings at surgery or autopsy, but may come to surgical excision due to hemorrhage or its large size. It has been suggested that estrogen therapy may lead to enlargement of the tumors. Rarely, thrombotic events within a large hemangioma may be associated with thrombocytopenia. These tumors can occasionally be multiple in the liver, and also can be associated with hemangiomas at other sites as part of Von Hippel-Lindau disease or skeletal/systemic hemangiomatosis syndrome.

Gross features. Hemangiomas are well circumscribed, red to red-brown tumors. They almost always have a spongy texture or honeycombed surface that represents the cavernous vascular component, and many will also have undergone thrombosis and sclerosis, which results in a firm, white to white tan appearance.

Microscopic features. The hallmark of this tumor is the cavernous vascular channels. The walls of these channels consist of fibrous stromal bands, which are lined by a single layer of flattened endothelial cells without cytologic atypia or mitotic activity. Sclerotic zones can be present and can be quite extensive. Thrombosed channels can also be seen. Extensively sclerotic hemangiomas may only have a few remaining vascular channels, and so can mimic a localized scar.

Angiomyolipoma

Clinical features. Angiomyolipomas (AML) are only rarely noted in the liver. The tumor often presents in the 30 to 40-year-old age group in men or women of varying ages. Some of these tumors occur in the setting of tuberous sclerosis, but many do not. The tumor is thought to arise from the perivascular epithelioid cell, and related lesions in other organs include the clear cell "sugar" tumor and lymphangioleimyomatosis of the lung.

Gross findings. AML can present as a large, variably colored tumor due to fat, necrosis, and hemorrhage.

Microscopic findings. This lesion usually is composed of various elements including smooth muscle-like cells, blood vessels, fat, and hematopoietic tissues. The smooth muscle-like differentiation is often the most prominent in liver AML, and consists of either epithelioid or spindled cells which often surround the vessels. The epithelioid cells have a rounded or polygonal shape with abundant eosinophilic cytoplasm. The nuclei are typically large and round with prominent nucleoli, but their appearance can vary. The cytoplasmic contents may be oncocytic, and may be condensed around the nucleus with a clear zone near the cell membrane, giving the appearance of a "spider-web". The spindled cells have eosinophilic cytoplasm and small oval nuclei. Trabeculae, usually composed mostly of the epithelioid type of cells have also been noted. Either the epithelioid or spindle cell component may predominate to the exclusion of the other. The vascular component is typically made up of thick-walled arterial or venous-like channels admixed with thin-walled venous-like spaces. The fatty tissue consists of mature fat cells scattered throughout the tumor as single, clusters, or sheets of cells; however, in the liver variants of this lesion, the fat component can be scant or absent. Foam cells containing fine-droplets of lipid can also often be seen. Peliotic spaces closely associated with areas of hemorrhage can be present. These paces mostly lacked an endothelial lining. Prominent dense lymphoid aggregates composed of a mixture of T and B cells can be noted as well. Rarely, the inflammatory cells can be associated with the stromal spindle cell component of the tumor, mimicking inflammatory pseudotumor. Rarely, hemosiderin and melanin pigments can be present. Variable numbers of hematopoietic elements including megakaryocytes, erythroid and myeloid precursors are often present.

Special studies. Most of the diagnostic problems arise when the epithelioid smooth muscle-like cells predominate within the tumor as the large round nuclei with prominent nucleoli and abundant eosinophilic cytoplasm mimics HCC or hepatic adenoma. In addition, any formation of trabeculae containing the epithelioid cells closely mimics HCC. Immunohistochemistry can thus be very helpful to identify the tumor as angiomyolipoma rather than HCC or adenoma by demonstrating positivity for HMB-45 and smooth muscle actin (SMA) in the smooth-muscle-like cells. The spindle cells often stain stronger for the SMA while the epithelioid cells for the HMB-45. Desmin positivity has been noted in the spindle cells as well. Stains for keratin are negative. S-100 has been noted to be focally positive in angiomyolipoma as well, generally staining the epithelioid and fat cells. The combination of spindled and epithelioid cells can also mimic metastatic melanoma, so the HMB-45 positivity of AML can add to the confusion.

Inflammatory Pseudotumor

Clinical features. Inflammatory pseudotumor (IPT) is a rare, inflammatory and fibrosing lesion that can be found in other organs besides the liver. Patients may present with abdominal pain, fever, chills, jaundice, vomiting, and weight loss. The lesions have also been reported associated with chronic cholangitis. The lesion can be mistaken clinically for cholangiocaricnoma if the lesion is in the hilar region. Evidence for Epstein-Barr virus has been noted in tumors from various sites, including the liver. Some have also suggested the possibility of an association with the proliferation of the follicular dendritic reticulum cells.

Gross features. The appearance can vary considerably, especially in the larger lesions, with foci of fibrosis, hemorrhage, and necrosis present. The tumor can vary considerably in size, may be solitary or multiple, and may arises either in the porta hepatic or elsewhere in the liver parenchyma.

Microscopic features. IPT consists of a mixture of inflammatory and fibrous tissue, but the relative degree of these components can be variable. The inflammatory component of the lesion usually contains a polyclonal population of plasma cells, but neutrophils, eosinophils, lymphocytes (predominantly T cells), and macrophages (often xanthomatous) are also often present to some degree. The spindle cell component is made up of fibroblasts, and sclerotic foci are common. Mitotic figures may be seen but should not be numerous, and abnormal mitotic figures should not be seen. Occasionally, granulomas or phlebitis (or varying degrees of venous obstruction) may also be present.

Special studies. The IPT should be differentiated from other sarcomas such as angiosarcoma or metastatic gastrointestinal stromal tumor. In these sarcomas, cellular atypia, frequent mitotic figures should be noted, and the sarcomas typically lack numerous inflammatory cells. Immunohistochemistry can be helpful as well, as angiosarcomas stain positively for Factor VIII and other vascular endothelial markers and metastatic gastrointestinal tumors react with CD117 and CD34. The differentiation from follicular dendritic cell (FDC) tumor may be more difficult, but the absence of plasma cells and the presence of pleomorphic tumor cells in FDC as well as specific markers for FDC such as CD21, CD35, and R4/23 should help distinguish the two lesions.

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