Case of the Month
January 2017 - Presented by Dr. Dongguang Wei & Dr. Kristin Olson
Definition of Angiomyolipoma
Angiomyolipoma (AML) is defined as a triphasic tumor composed of three components: thick-walled blood vessels, adipose tissue, and smooth muscle (spindled or epithelioid) tissue. It is a benign mesenchymal neoplasm arising from perivascular epithelioid cells that usually demonstrates myomatous, lipomatous differentiation and melanogenesis.
As a triphasic tumor, the histologic features of AML may vary extensively according to its tissue composition. Diagnostic challenge arises when some components are scant/dominant or when the specimen is not properly sampled. The hepatic AML may mimic smooth muscle tumors, primary liver tumors, and vascular malformations. It can also be mistaken for other mesenchymal tumors. The key to a correct diagnosis is searching for the three major components, sufficient sampling of representative lesions. If histology is not conclusive, IHC can aid in making the proper diagnosis. In general, AML is typically positive for melanoma markers (HMB-45, Melan-A) and, in contrast, the other tumors are negative with the exception of melanoma. As a mesenchymal neoplasm, AML is negative for epithelial markers (cytokeratin).
Primary hepatic AML is usually asymptomatic and found incidentally on imaging study. Patients are usually 30 to 40 years of age, and disease distribution is equal between the sexes. It is usually found in the right lobe. Patients may present with non-specific symptoms like malaise, fatigue, anorexia, abdominal pain, or an abdominal mass. Patients with large subcapsular AMLs may present with rupture and hemorrhage. Liver function tests are usually normal, and serum tumor markers are negative. Imaging studies of US, CT, and MRI typically demonstrate the fat component and prominent central vessels. At US, AML could be highly echogenic and indistinguishable from a hemangioma. On CT scan, it usually demonstrates a well-demarcated, radioluscent mass. Since CT is insensitive to the small amount of fat within hepatic AMLs, the results on CT are often nonspecific. MRI usually shows high signal intensity on T1-weighted images. On T2-weighted sequences, it could be homogeneously or heterogeneously hyperintense. On fat-suppressed T2-weighted images, it contains areas with low signal intensity likely due to muscle and fat components. On contrast-enhanced MRI studies, it shows intense heterogeneous enhancement in the arterial phase, and may show a delayed washout phenomenon. AMLs reveal its hyper vascular elements on angiographic study. These imaging characteristics may help to achieve a preoperative diagnosis of AML. Fine-needle aspiration biopsy confirms the diagnosis. When the tumor is large and symptomatic, surgical resection is usually considered because of the potential for local invasive growth and the low recurrent rate after resection. Hepatic AML usually have coexisting renal AM. Patients, who have germ line mutations in the genes coding tuberin (TSC2), are more likely to have hepatic AML.
On gross examination, the hepatic AMLs are usually solitary, but occasionally can be multiple on a background of normal hepatic parenchema. Most of the cases are well circumscribed and globular with or without a capsule. The components of adipose tissue, muscular, and vascular elements determine its color and consistency: from homogeneous yellow to variable red-yellow-tan in color and from firm to fleshy in texture. Some tumors may become quite large (up to 40 cm in diameter), foci of hemorrhage and necrosis could be found within these large tumors.
Microscopic appearance can be quite variable from case to case, especially those with a predominant single component, which may be a diagnostic challenge. Typical microscopic features are: a mixture of mature adipose tissue, thick-walled, often hyalinized arteries, prominent smooth muscles and hematopoietic elements. The variable amount of adipose tissue is usually organized in sheets or scattered throughout the tumor. The fat component could also be scant or even absent. Foam histiocytes containing fine droplets of lipid, often are seen. The smooth muscle component, usually more prominent in hepatic AMLs than in renal AMLs, shows sheets and bundles of eosinophilic spindle cells surrounding blood vessels or swirling off the periphery of thick walled vessels. Some of the myoid cells are polygonal or rounded (epithelioid) with finely granular, eosinophilic cytoplasm. Cytologic atypia may be seen. The epithelioid or spindle cell component may predominate in any AML. Ultrastructural study shows myofilaments, large electron-dense bodies, and glycogen and lipid droplets in these cells. Melanin pigment may also be present. The epithelioid myoid cells may mimic HCC, renal cell carcinoma, sarcoma, and melanoma. The vascular entity usually shows numerous tortuous, thin-walled vascular channels/sinuses and variable numbers of thick-walled arteries demonstrating hyalinization and/or intimal proliferation, Most hepatic AMLs contain hematopoietic elements, if these elements are large enough, the tumor may be referred to as angiomyomyelolipoma. Actually extramedullary hematopoiesis is a frequent feature of hepatic AMLs. Some cases contain dense lymphoid aggregates or prominant chronic inflammatory components (usually mononuclear cells), which mimic the inflammatory pseudotumour or lymphoma.
Immunohistochemistry (IHC) is a very helpful to confirm the mesenchymal nature of the tumor. The entire tumor is typically negative for cytokeratin. However, the defining myoid cells show immunoreactivity for HMB-45 (nearly all tumors), smooth muscle actin (SMA) and other melanogenosis marker such as melan-A. These immunohistochemical features are characteristic to identify AML and to rule out HCC and/or adenoma. Although HMB-45 positivity spindle and epithelioid cells may mimic metastatic melanoma, other melanoma markers may be useful in this situation. The typical staining pattern is: spindle cells often stain more strongly for SMA, whereas epithelioid cells stain for HMB-45. Desmin staining was also observed in spindle cells. S100 (another melanogenosis antigen) is only focally positive for epithelioid and fat cells. CD68 is also positive. Other markers such as CD117 (c-kit), desmin, calponin, and vimentin show variable expression in myoid elements. The vascular elements of AML are positive for CD31, CD34, and Factor VIII.
AMLs with a predominantly smooth muscle component can show morphologic overlap with leiomyoma or leiomyosarcoma. Morphologically, the spindle shaped smooth muscle component of AML may resemble the leiomyoma or leiomyosarcoma by demonstrating a spindle cell nature, especially in the setting of a small volume biopsy material. A definitive clue is that the smooth muscle cells of AML stain positively (at least should be patchy positive) for HMB-45, however, the spindle cells in leiomyomas and leiomyosarcomas do not stain. Observation of other histologic features of leiomyosarcoma, such as lack of triphasic appearance, poorly circumscribed tumors with infiltrative borders, and high-grade, malignant cytologic features, and presence of mitotic activity will lead to the correct diagnosis.
Hepatocellular carcinoma or hepatic adenoma
In AML cases when epithelioid smooth muscle cells show trabecular architecture or when epithelioid smooth muscle cells predominate in the tumor or on biopsy specimens (“tumor giant cells”), a differential diagnosis of hepatocellular carcinoma (HCC) or hepatocellular adenoma (HCA) should be raised. The epithelioid smooth muscle cells with large, round nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm could be mistaken for HCC and hepatic adenoma. In real practice, many hepatic AML cases are submitted for consultation with those preliminary diagnoses. Clinical history of cirrhosis, lack of triphasic appearance, active mitotic activity, positive staining for CAM 5.2, HepPar-1, CEA, and GPC-3 favors the diagnosis of HCC. Presence of HMB45, Melan-A, SMA/desmin staining, along with the absence of abovementioned staining supports the diagnosis of angiomyolipoma.
Patients usually have past medical history of exposure to vinyl chloride. The angiosarcoma is usually a dark red to brown colored irregular shaped lesion, with hemorrhagic/necrotic and cystic change, and spongy texture. Satellite nodules are present. Histologic features include: spindle cell predominant lesion, sinusoidal growth pattern with solid and/or papillary feature at the peripheral part of the tumor. Vascular invasion is frequently seen. Angiosarcoma is positive for vascular endothelial markers like CD31, CD34, and factor VIII. However, it is negative for HMB45, Melan-A.
Patients usually have past medical history of melanoma; histologic feature of melanoma includes marked cytologic atypia with prominent nucleoli, high mitotic rate, and lack of triphasic appearance. Importanly, the presence of HMB-45 immunoreactivity does not imply a diagnosis of metastatic melanoma. The melanoma shows strong, diffuse S100 staining, however, AML usually reveals variable weak to negative S100 staining. Finally, metastatic melanoma lacks myoid, lipoid and prominent vascular components and is usually negative for the related markers like SMA/desmin/vimentin, CD31, CD34, and Factor VIII.
Malignant hepatic AML
Malignant variant of hepatic AML is extremely rare, definitive criteria for malignant AML have not been established yet. It is difficult to prove with traditional criteria: i.e., the presence of tumor cells in abdominal lymph nodes does not prove a metastasis as multicentric lesions of AML have been reported. Malignant AML may be a transformation from benign hepatic AML. It may show the classic histologic/molecular feature of benign AML. However, features that differentiate malignant AML from benign AML are: it is usually large-sized tumor, it also demonstrates foci of high-grade nuclear atypia, high mitotic rate, abundant tumor coagulative necrosis, vascular/hepatic parenchymal invasion, and distant organ metastasis. One unique feature is: some malignant AMLs are positive for P53 staining, but classic AML does not show reactivity to P53. Therefore, large tumor size, high-grade atypia, frequent and atypical mitotic figure, necrosis, P53 immunoreactivity, vascular invasion, and distant organ metastasis should raise the concern for malignancy.
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