Case 4 -

Embryonal Sarcoma of the Liver Cheryl M. Coffin Primary Children's Medical Center University of Utah Salt Lake City, Utah

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Clinical History A 14-year old girl was found to have a mass in the liver. She underwent an extended right hepatic lobectomy. She received chemotherapy with vincristine, adriamycin, actinomycin-D, and Cytoxan for one year. 20 months and 38 months after the initial diagnosis she had pathologically documented metastases in the right lung, and these were resected. She was alive and well twenty years after initial diagnosis. Case 4 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 4 - Figure 1 At low power, the embryonal sarcoma of the liver contains extensive areas of myxoid degeneration and coagulative necrosis surrounded by a proliferation of atypical spindled and polygonal cells. Case 4 - Figure 2 The tumor cells form sheets and vague fascicles and display nuclear pleomorphism and hyperchromasia. Case 4 - Figure 3 Strands of tumor cells are dispersed in a loose myxoid background. Case 4 - Figure 4 The pleomorphic hyperchromatic tumor cells show frequent and atypical mitoses. Case 4 - Figure 5 In a more cellular areas, variations in cytomorphology are notable, with ovoid, epithelioid, and spindled tumor cells. Case 4 - Figure 6 PAS-positive intracellular and extracellular hyaline globules are present focally. Case 4 - Figure 7 - A1ACT Strong diffuse cytoplasmic reactivity for alpha-1 anti-chymotrypsin is present in tumor cells. Case 4 - Figure 8 - p53 Diffuse nuclear p53 reactivity is present in tumor cells and may reflect a mis-sense mutation of p53. Pathologic Features The partial hepatectomy and cholecystectomy specimen weighed 2,510 g and measured 21 x 20 x 10 cm. A tumor involved the entire width of the resection and had a mucoid and firm, white, tan and focally hemorrhagic, variegated cut surface. Histologically the tumor contains extensive areas of coagulative necrosis, hemorrhage, and myxoid degeneration, with foci of cystic change lined by tumor cells. The cellularity in the preserved areas varies from moderate to high. The tumor cells are polygonal to spindled with nuclear atypia and pleomorphism, occasional large eosinophilic nucleoli, individual cell necrosis, and pale eosinophilic cytoplasm with indistinct cell borders. Occasional large, lobulated, hyperchromatic tumor cells are seen, and multinucleated tumor cells are present. Some of the tumor cells contain eosinophilic globules in the cytoplasm, and extracellular hyaline globules are also seen. The mitotic rate is greater than 20 per 10 high power fields in the most cellular, mitotically active areas. Atypical mitoses are present. Focally, hepatocytes and bile ducts are entrapped within the tumor, especially in areas near the fibrous pseudocapsule. PAS stains with and without diastase demonstrate PAS-positive, diastase resistant globules and granules in tumor cell cytoplasm and in the extracellular matrix. Immunohistochemical stains were performed with appropriately reactive controls. The tumor cells showed strong diffuse cytoplasmic reactivity for alpha-1-antitrypsin and alpha-1-antichymotrypsin. Diffuse nuclear p53 reactivity was present. There was no reactivity for alpha-fetoprotein, muscle-specific actin, desmin, myogenin, or h-caldesmon. Electron microscopy was performed and revealed primitive mesenchymal spindle cells in a mucoid matrix with collagen. The tumor cells contained abundant rough endoplasmic reticulin, numerous fat droplets, and occasional primitive junctions. No intermediate filaments, glycogen aggregates, or basal lamina were identified. Discussion This represents an embryonal sarcoma (undifferentiated sarcoma) of the liver. The case was selected to highlight the clinicopathologic features of this rare hepatic neoplasm, to discuss the spectrum and differential diagnosis of hepatic neoplasms of childhood, and to review the hypothetical relationship to mesenchymal hamartoma of the liver. Primary hepatic neoplasms are rare in children (Table 1). In the SEER Registry between 1973 and 1997, there were 271 primary hepatic malignancies reported in the United States in patients less than 20 years of age. Among these, 67% were hepatoblastomas, 31% were hepatocellular carcinomas, and the remaining 2% were other tumors, including embryonal sarcoma of the liver. In this series, 91% of the hepatoblastomas occurred in children less than 5 years of age at diagnosis, and 87% of hepatocellular carcinomas occurred in the 15 to 19 year age range. During this 25 year period, the rate of hepatoblastoma doubled and the frequency of hepatocellular carcinoma decreased. In a review from the AFIP of malignant hepatic tumors in patients from birth to 20 years of age, embryonal sarcoma accounted for 13% of malignancies and occurred predominantly in the 5 to 20 year age group. In contrast, embryonal sarcoma of the liver accounted for 6% of primary benign and malignant hepatic tumors in childhood in the series from Texas Children's Hospital. The pathologic evaluation of primary pediatric hepatic neoplasms is critical for diagnosis and staging. The gross specimen should be weighed, measured, and photographed, and the number and size of tumor nodules documented. The color, consistency, texture (with solid versus cystic areas), and the presence of hemorrhage, calcification, and necrosis should be included in the macroscopic description. Margins should be inked. Sections include the tumor, margins, interface between tumor and normal liver, hilar lymph nodes, and hepatic vessels. The guideline for histologic sampling is one section per centimeter of tumor diameter. Tissue should also be obtained for special studies including cytogenetics, molecular genetics, electron microscopy, and other purposes. Embryonal sarcoma of the liver has also been referred to as undifferentiated sarcoma and malignant mesenchymoma in the past. In the current WHO classification of hepatic tumors, the preferred term is embryonal sarcoma, which is defined as a malignant tumor composed of mesenchymal cells that by light microscopy are undifferentiated. Clinically, embryonal sarcoma of the liver occurs in later childhood, with a peak between 6 and 10 years of age and an age range that spans infancy to old age. The largest published series included 31 cases reported from the Armed Forces Institute of Pathology by Stocker and Ishak in 1978. The clinical presentation is a rapidly growing abdominal mass with or without pain, fever, jaundice, and an elevated leukocyte count. Males and females are equally affected and the tumor has a predilection for the right lobe of the liver. Laboratory findings are nonspecific and serum alpha-fetoprotein is normal. Embryonal sarcoma can invade the vena cava and extend into the right atrium, mimicking a primary cardiac neoplasm. Individual examples of embryonal sarcoma have been associated with prenatal phenytoin exposure, the Li-Fraumeni family cancer syndrome, and as a second malignant neoplasm following treatment for Hodgkin disease. Stages 1 through 4 are defined by the Children's Cancer Study Group Staging Classification System (Table 2). Imaging findings vary with the modality. Plain film and barium studies reveal a right upper quadrant abdominal mass with or without calcification. Ultrasound demonstrates a heterogenously solid mass with or without calcification or a multiseptated cystic mass. CT scans show a hypodense mass; myxoid areas have lower attenuation and solid areas are more dense. MRI scans reveal heterogenous signal intensities reflecting the cystic, myxoid, and solid areas that are seen pathologically. Angiographic findings are nonspecific. In some cases there may be a discrepancy between ultrasound findings, which demonstrate a solid mass, and CT or MRI findings, which have a more cystic appearance due to low attenuation areas. Macroscopically, embryonal sarcoma of the liver is a large, solitary, well-demarcated non-encapsulated tumor with a globular shape. Typically the tumor ranges from 10 to 20 cm in diameter, although larger tumors have been reported. The right lobe of the liver is more frequently involved. The mass has a fibrous pseudocapsule and a variegated surface with glistening solid grey-white tumor tissue alternating with cystic, gelatinous, hemorrhagic, and necrotic areas. Cystic change is associated with myxoid degeneration, hemorrhage, and necrosis. Microscopically, embryonal sarcoma of the liver is composed of malignant stellate, ovoid, epithelioid, or spindle cells that are compactly or loosely arranged in a myxoid stroma. The sarcomatous cells are packed in sheets and whorls and have numerous mitoses. The cytoplasm is lightly eosinophilic. The tumor cell nuclei vary in size and shape with hyperchromasia, large bizarre tumor cells, and multinucleated tumor cells. The variably sized cytoplasmic and extracellular eosinophilic globules are PAS positive and diastase resistant. These globules probably represent apoptotic bodies that have been phagocytosed. At the periphery of the tumor, particularly in areas near the fibrous pseudocapsule, entrapped bile ducts and hepatocellular elements are seen. Some of the bile ducts may have a degenerating or hyperplastic appearance. Organizing and recent thrombi may be found, especially in areas of hemorrhage and necrosis. Foci of hematopoiesis may be seen. Fine needle aspiration cytology shows bizarre anaplastic cells, giant tumor cells, and spindle cells with marked variation in morphology. Immunohistochemistry reveals widely variable and non-specific reactivity for vimentin, alpha-1 antitrypsin, and alpha-1 antichymotrypsin in tumor cells and variable reactivity for cytokeratin, desmin, muscle specific actin, and neuron-specific enolase. Ultrastructurally, tumor cells contain rough endoplasmic reticulum with dilated cisternae containing amorphous material, variable intermediate filaments and cell junctions, and a prominent extracellular matrix with occasional collagen fibers. Cytogenetic and molecular genetic abnormalities in embryonal sarcoma include many numerical and structural cytogenetic abnormalities, but no specific abnormality that appears to be characteristic. Both aneuploidy and diploidy have been detected with flow cytometry. The more frequent changes include gains of chromosomes 1q, 5p, 6q, 8p, 11q, and 12q and losses of chromosomes 9p, 11p, and 14. Strong p53 reactivity and mis-sense mutations of p53 have been identified in 3 cases of embryonal sarcoma of the liver and have not been found in mesenchymal hamartoma. The prognosis for embryonal sarcoma of the liver was poor in older series, with patients seldom living for more than a year. More recently, better survival has resulted with surgical resection and chemotherapy with or without radiation therapy. Preoperative chemotherapy has been used successfully to diminish the size of large embryonal sarcomas of the liver and allow later complete surgical resection. With sarcoma-like chemotherapy and complete tumor resection, survival periods of 2.4 to 20 years were achieved in a series of Italian patients, and a 37% three-year survival rate was reported in a German series. The histogenesis of embryonal sarcoma of the liver has been debated, with fibrous histiocytoma, sarcomatoid hepatocellular carcinoma, and the malignant analogue of mesenchymal hamartoma postulated in the past. The possibility of embryonal sarcoma of the liver must be considered in children and adolescents with a liver mass, especially in those greater than 5 years of age at presentation. Differential diagnostic considerations include mesenchymal hamartoma (Table 3), embryonal rhabdomyosarcoma of the biliary tract, yolk sac tumor of the liver, angiomyolipoma, leiomyosarcoma, fibrosarcoma, hepatoblastoma, and hepatocellular carcinoma. 85% of mesenchymal hamartomas of liver are diagnosed in the first two years of life and only 5% after five years of age. CT and MRI scans reveal a multicystic mass, and the right lobe is involved in 75% of cases. Mesenchymal hamartoma displays a loose myxoid stroma populated by spindle or stellate cells without atypia or mitoses. These mesenchymal cells are organized around benign epithelial duct-like biliary structures, that are frequently cystic, and are mixed with bland areas of hyaline fibrosis. The biliary structures resemble ductal differentiation or the ductal plate malformation. Islands of hepatocytes may be seen within the fibrous tissue. Cystic areas with unlined walls, extramedullary hematopoiesis, and immunohistochemical reactivity for desmin and actin in the stromal cells are seen. Cytogenetic findings reported in a few cases of mesenchymal hamartoma include balanced translocations between chromosome 19q13-15 and other partners, including chromosomes 11 and 15. Rare combined pattern tumors with features of both embryonal sarcoma and mesenchymal hamartoma have raised the question of whether mesenchymal hamartoma is capable of malignant evolution to embryonal sarcoma of the liver or whether there is simply some morphologic overlap in a small number of cases. Among four cases of embryonal sarcoma with focal features of mesenchymal hamartoma, three occurred in adolescents, and one arose in a three-year old boy. These cases had varying proportions of histologic areas with features of embryonal sarcoma and mesenchymal hamartoma, with transition zones at the interface between the two tumors. Two of the cases also had foci of ectopic adrenal tissue observed beneath Glisson's capsule. Flow cytometry of different areas revealed diploidy in the mesenchymal hamartoma foci and aneuploidy in areas of embryonal sarcoma. Karyotypic abnormalities observed in two of these cases included structural alterations of chromosome 19q13.3-13.4. Embryonal rhabdomyosarcoma of the biliary tract typically has botryoid features and displays pattern of growth associated with bile ducts rather than a primarily intrahepatic mass. The grape-like projections into the biliary duct lumina are characteristic. Histologically, a cambium layer of rhabdomyoblasts and strap cells beneath epithelium and reactivity for myogenin, myo-D1, muscle-specific actin, and desmin are typical. Yolk sac tumor of the liver can rarely occur in children and is distinguished from embryonal sarcoma of the liver by a combination of histologic features, serum alpha-fetoprotein elevation, and reactivity for alpha-fetoprotein. Hepatoblastoma and hepatocellular carcinoma have distinctive clinical and histologic features in most cases that allow ready distinction from embryonal sarcoma of the liver. Primary hepatic leiomyosarcoma and fibrosarcoma are rare in children and could be distinguished by a combination of histologic features and immunohistochemistry. Angiomyolipoma can contain large bizarre cells, but is similar to other perivascular epithelioid cell neoplasms in its immunohistochemical reactivity for melanocytic markers such as HMB45 and S100 protein. In the past malignant mesenchymoma of the liver was used when two definite types of mesenchymal differentiation other than fibrosarcoma were identified, but this neoplasm is extremely rare, and the diagnostic term is seldom used. Table 1. Primary Hepatic Malignancies in Childhood and Adolescence: Summary of Three Series SEER [6] AFIP [26] TCH [30] Total Cases 271 409 46 Time Period 1973-1997 1970-1999 1956-1984 Age Range NB-20 yr NB-20 yr Pediatric Tumor Types Hepatoblastoma 67% 48% 59% Hepatocellular carcinoma 31% 33% 24% Embryonal sarcoma NA 13% 17% Angiosarcoma NA 4% NA Embryonal rhabdomyosarcoma NA 2% NA Other 2% 0 NA Table 2. CCSG Staging of Embryonal Sarcoma of the Liver [25] Stage Definition I Complete resection II Microscopic residual disease Negative lymph nodes No spilled tumor III Gross residual " nodal involvement " spilled tumor Complete resection with lymph nodes positive, tumor spillage, or both Incomplete resection with lymph nodes positive, tumor spillage, or both IV Metastatic disease Table 3. Comparative Features of Embryonal Sarcoma and Mesenchymal Hamartoma of the Liver Feature Embryonal Sarcoma Mesenchymal Hamartoma Median age 8 years 10 months Male: Female ratio Equal 2:1 Symptoms Mass, pain Abdominal enlargement Gross Pathology Mass with necrosis, hemorrhage, and myxoid foci Mass with fluid-filled cysts Pedunculation 3% 17-30% Mesenchyme Pleomorphic, anaplastic Absent Tumor giant cells Present Absent Bile ducts Entrapped Integral Hepatocytes Entrapped Entrapped PAS-positive globules Present Absent Hematopoiesis 50% 87% Genetic aberrations -Aneuploid -Nonspecific gains and deletions -p53 mutation -Diploid -Translocations at 19q13.3-4 -No p53 abnormality Prognosis Guarded Excellent References Babin-Boilletot A, Flamant F, Terrier-Lacombe MJ, et al. Primitive malignant nonepithelial hepatic tumors in children. Med Pediatr Oncol 1993; 21:634-639. Begueret H, Trouette H, Vielh P, et al. 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