Case 1 -

Pericardial Immature Teratoma with Malignant Yolk Sac Tumor Component Debra L. Kearney Texas Children's Hospital Houston, TX

Click on each slide thumbnail image for an enlarged view

Clinical History Prenatal ultrasound of an 18 weeks gestation female fetus revealed a mediastinal mass and pericardial effusion. The mass was not evident by ultrasound at 14 weeks gestation. Fetal echocardiography demonstrated a moderate pericardial effusion and a 1.8 x 1.4 cm, predominantly solid, extracardiac tumor that was closely related to the right side of the ascending aorta and compressed the superior vena cava and atrium. The pregnancy was terminated at 19 weeks gestation. Case 1 - Figure 1 - Heart in-situ with large well circumscribed mass overlying right atium. On right a probe elevates the mass exposing the compressed, distorted right atrium Case 1 - Figure 2 - A transverse, cross section of the thorax. Right and left lungs are connected by the branch pulmonary arteries with a cross section of the ascending aorta situated near the left lung hilum. The tumor is attached to the anterior and rightwards border of the aorta. The tumor has a fleshy, tan-white cut surface with two central cystic spaces and focal hemorrhage. The section is taken superior to the heart Case 1 - Figure 3 - A low power (2x), H & E section through the tumor demonstrating the point of attachment to the root of the aorta (the large vessel in the central-top portion of the image). The tumor has a heterogeneous composition. Myocardium of the right ventricular outflow tract is evident in the right upper corner of the image and is not infiltrated by tumor Case 1 - Figure 4 - H & E sections of the tumor demonstrating the heterologous composition with attempted organogenesis. The image to the left shows a cystic space lined by ciliated respiratory epithelium with surrounding mesenchyme and smooth muscle simulating a bronchiole (40x). On the right, the top image shows a nodule of cartilage (20x) and the bottom shows striated muscle (40x). The middle image shows pancreatic tissue with acini and islets (20x) Case 1 - Figure 5 - A medium power (10x) H & E section of the tumor demonstrating, on the left, a large cystic space lined by hyperchromatic, immature neuroepithelium simulating the neural tube. The neuroepithelium merges with irregularly shaped tubules lined by columnar and cuboidal epithelium, all dispersed within a moderately cellular, pale staining, immature mesenchyme Case 1 - Figure 6 - A low power (2x) H & E section of the tumor demonstrating aggregates of tubules, and solid nests and cords of cells disposed within a stroma that varies in cellularity and density. The very pale, nearly clear, mucinous regions of the stroma should be closely examined for the presence of yolk sac tumor Case 1 - Figure 7 - H & E images of the clear, mucinouspale areas of stroma show solid nests (right image 10x), cords and loosely dispersed tumor cells (left image 4x) of yolk sac tumor (left 4x, right 10x) Case 1 - Figure 8 - High power, (40x) H & E images of monotonous, tumor cells with a delicate nuclear chromatin pattern, occasional nucleoli, and scant, relatively clear cytoplasm of malignant yolk sac tumor Case 1 - Figure 9 - High power (40x) H & E image of hepatic differentiation. The image on the left shows areas of the teratoma with immature fetal liver morphology with congestion/hemorrhage within sinusoids. The image on the right shows clusters of hepatoid pattern of yolk sac tumor surrounded by typical yolk sac tumor morphology Case 1 - Figure 10 - Intermediate power (20x) H & E image of primitive endodermal glands representing well differentiated yolk sac tumor. The glands are lined by cells with basal, subnuclear vacuoles and are dispersed within immature stroma Differential diagnosis of Congenital Cardiac/Pericardial Tumors Rhabdomyoma Teratoma (mature/immature/malignant) Fibroma Hemangioma/Lymphangioma Lipoma/Lipoblastoma Myocardial Hamartoma (Purkinje cell tumor/Histiocytoid cardiomyopathy) Rhabdomyosarcoma Fibrosarcoma Blood cysts Epithelial cysts (Heterotopias/Foregut cysts) Myxoma Diagnosis: Pericardial immature teratoma with malignant yolk sac tumor component. Discussion: Postmortem findings: Fetal and placental development were appropriate for gestational age. Within the pericardial cavity a 1.5 x 1.8 x 1.3 cm, mottled gray-purple-brown, predominantly solid mass was firmly attached to the right lateral border of the aortic root, displacing the heart into the left hemithorax. The tumor was larger than the adjacent heart and significantly compressed the superior vena cava and right atrium. (Figure 1). The cut surface of the tumor was mottled, grey and predominantly solid with two small, 0.3 cm centrally located cysts (Figure 2). The heart was structurally normal and was not invaded by the tumor. Although both lungs were also compressed by the tumor and displaced heart, they were well developed with normal lung volumes for age. Fetal hydrops was not evident and the placenta was of normal size. Microscopically the tumor was confluent with the visceral and parietal pericardium at the aortic root (Figure 3). It was comprised of an admixture of mature and immature tissue types, derived from endodermal, mesodermal and ectodermal layers. Mature tissues included squamous and columnar epithelium, pancreas, striated muscle, ganglion cells, retina and cartilage (Figure 4). Immature mesenchyme was the predominant immature component with scattered clusters of primitive neuroepithelium forming neural tube-like structures (Figure 5). The two grossly evident cysts were also predominantly lined by primitive neuroepithelium. (Figure 3). In many areas the tumor had a loose, myxoid matrix containing irregular nests and ribbon-like clusters of malignant cells with high N/C ratio and occasional prominent nucleoli, typical of yolk-sac tumor (Figures 6-8).Also present were foci of hepatic differentiation and primitive endodermal glands, patterns suggested to represent "well-differentiated yolk sac tumor". The immature hepatocytes were frequently intimately admixed with typical yolk-sac tumor (Figure 9). The primitive endodermal glands with basal, subnuclear vacuoles were located within immature stroma. (Figure 10) Congenital cardiac tumors are defined as those that present within the first 3 months of life. Presenting clinical symptoms are related to tumor location and size and include: Pericardial effusions and cardiac tamponade Hydrops fetalis Congestive heart failure Cardiac arrhythmia Stillbirth The most common prenatally (>60%) and postnatally diagnosed cardiac tumor is rhabdomyoma. Most are asymptomatic, discovered on routine obstetric ultrasound. These are solid, frequently multiple, intracardiac tumors, most often located within the ventricles. They may be intramural, intracavitary or valvular. The typical histology shows clusters of large, glycogen filled myocytes with sparse myofibrils radiating from the central nucleus ("spider cells"). These lesions are considered to be hamartomas and frequently spontaneously regress by 2-4 years of age. 50-70% are associated with tuberous sclerosis. This incidence is likely to be even higher since the associated extracardiac manifestations of this autosomal dominant complex are usually not manifest in the perinatal period. In the fetus, teratomas are second in frequency to rhabdomyomas, and are either second or third in the neonate. Most arise from the pericardium, although intracardiac tumors (atria, ventricular freewall and septum) rarely occur. Most are detected prenatally (20 – 40 weeks gestation) and nearly all are associated with a pericardial effusion, attributed to localized obstruction of venous inflow into the heart and/or direct obstruction of cardiac/pericardial lymphatic drainage. The tumors are frequently large, cystic and most are composed of an admixture of mature, well differentiated tissues and variable amounts of immature neuroepithelium and mesenchymal stroma. Rapid in-utero tumor progression may occur with the onset of hydrops fetalis and cardiac tamponade. These features portend a poor prognosis. In-utero pericardiocentesis (evacuation of pericardial fluid and tumor decompression) has been successfully performed, permitting further maturation of the fetal lungs prior to delivery. The effusion tends to reaccumulate, necessitating repeat drainage. Fetal surgery has also been successful in excising the tumor; however this may not resolve the hydrops fetalis and accompanying pulmonary hypoplasia may lead to neonatal death. Postnatal surgical resection is usually curative. Extragonadal teratoma is the most common perinatal tumor, most of which are sacrococcygeal (40%) followed by intracranial tumors (13%). Pericardial (and rarely intracardiac) localization occurs in 7-10%. Although most reports designate pericardial teratomas as being benign and mature, when microscopic features are provided, foci of immature neuroectodermal tissues are frequently described. (Pratt, et al 2000) Yolk sac tumor is the most frequent malignant component in teratomas at all locations. Other rarely reported malignancies include peripheral neuroectodermal tumors (in infants), other germ cell tumors such as germinoma, embryonal carcinoma, choriocarcinoma (in older children) and rarely epithelial carcinomas (adults). Although yolk sac tumor may rarely be found in mature teratomas, it has been reported > 25% of extragonadal immature teratomas. (Marina et al 1999) A recent review of congenital teratomas revealed immature elements in 75% and foci of yolk sac tumor in 30%. All 9 fetal cases had abundant immature neural elements and nearly 50% had microscopic yolk sac tumor. One of the 9 fetal teratomas was pericardial and contained yolk sac tumor. (Heerema-McKenney, et al, 2005) In the few reports of immature pericardial teratomas, microscopic foci of malignant yolk sac tumor are frequently described. (Roy et.al. 2004). Quantitation of the primitive neural component has been the basis for grading "immature teratomas", with documented increased risk for recurrence/metastasis in higher grade tumors of the ovaries in older children and adults. Although this relationship has not been demonstrated for extragonadal immature teratomas, (Marina 1999) high grade immaturity has been inappropriately equated with malignancy in intrapericardial teratomas. (Pratt, et al 2000) The presence of microfocal yolk sac tumor in 83% of high grade immature teratomas has led to suggestions that undetected yolk sac tumor in immature teratomas forms the basis for tumor relapse (Heifetz, 1998). In histologic sections, malignant yolk sac tumor tends to be regionally associated with the immature neuroectodermal tissues, thereby increasing the likelihood of this malignant component in high grade immaturity. (Heifetz, 1998) Several factors refute high grade immaturity and microfocal yolk sac tumor as being the primary basis for tumor relapse. Although in 50% of childhood teratomas that recur or metastasize, the histologic pattern of relapse may be yolk sac tumor, this occurs in both mature and immature teratoma. (Gobel 1998) Two thirds of relapsing tumors will show different histology from the original tumor, including complete maturation in a previously immature teratoma. (Gobel 1998, Herrema-McKenney 2005). In extragonadal teratomas, most of which occur in infants, the only universally accepted risk for recurrence/metastasis is incomplete tumor resection. (Heerema-McKenney 2005,Gobel 1998) Treatment for extragonadal teratomas is complete surgical excision. The degree of immaturity or the presence of yolk sac tumor does not alter therapy. Tumor recurrence in completely excised mature and immature teratomas occurs in < 10% of cases, and has been reported up to 3 years post-operative. (Goebel 1998) Monitoring with imaging studies and serum alpha-fetoprotein levels (a tumor marker for yolk sac tumor) are recommended. Chemotherapy is reserved for patients with recurrent yolk sac tumor with 80-100% subsequent survival. Most cardiac fibromas are asymptomatic in-utero, therefore when prenatal detection occurs it is usually due to an intracardiac mass seen on routine ultrasound. It is a benign solitary, slow growing, solid tumor, which in the fetus and neonate, most often involves the ventricular septum. Clinical symptoms depend upon specific location with reported manifestations including congestive heart failure, ventricular outflow obstruction, conduction defects with arrhythmias and sudden unexpected death (Isaac 2004) Grossly the tumor may be circumscribed or have indistinct borders. Histologically the borders are infiltrative with entrapped myocytes usually at the periphery. Calcification is frequent and large tumors may show central cystic degeneration and necrosis. The tumor is primarily composed of fibroblasts and collagen. In infancy, tumor cellularity is higher and may show mitotic activity with a more fibromyxoid stroma (Freedom 2000). Cellularity decreases with age, particularly in the central region, as more collagen and elastin are deposited. The tumor is may not be amenable to complete surgical resection; partial resection and cardiac transplantation are acceptable alternatives. Although the histogenesis of this tumor remains unknown it has been suggested to be part of the family of fibromatoses. The tumor is associated with Gorlin syndrome (nevoid basal cell carcinoma syndrome) an autosomal dominant condition. The findings in this syndrome are quite variable and the diagnosis may be missed in the absence of a family history (Coffin 1992). The most frequent findings in the newborn are rib or vertebral anomalies and a large head. These 3 congenital cardiac tumors illustrate several important distinctions associated with tumors in the neonate and infant as compared to older children and adults: The tumor may spontaneously regress Rhabdomyoma, hemangioma, lipoblastoma The tumor may be considered a hamartoma, rather than true neoplasm with limited potential for growth Rhabdomyoma, fibroma, hemangioma, myocardial hamartoma (histiocytic cardiomyopathy). The tumor may contain immature cellular elements that may undergo spontaneous maturation Teratoma The tumor may contain malignant elements which, contrary to their presence at an older age, may not behave in a biologically malignant fashion Teratoma The tumor may be associated with congenital syndromes Rhabdomyoma (tuberous sclerosis; Fibroma (Gorlin syndrome); Atrial myxoma (Carney complex) References Q.C. Ahou, P Fan, Q.H. Peng, M. Zhang, Z. Fu, C.H. Wang. Prenatal echocardiographic differential diagnosis of fetal cardiac tumors. Ultrasound Obstet Gynecol 2004; 23: 165-171. H. Isaacs Jr. Perinatal (fetal and neonatal) germ cell tumors. J Pediatr Surg 2004; 39(7):1003-1013. S.A. Heifetz, B. Cushing, R. Giller, J.J .Shuster, C.J.H .Stolar, C. Vinocur, E.P. Hawkins. Immature teratomas in children: pathologic considerations: a report from the combined pediatric oncology group/children's cancer group. Am J Surg Pathol 1998 22(9):1115-1124. R.M. Syodorak, T. Kelly, V.A. Feldstein, P.L. Sandberg, N.H. Silverman, M.R. Harrision, C.T. Albanese. Prenatal Resection of a fetal pericardial teratoma. Fetal Diagn Ther 2002; 17:281-285 U. Göbel, G. Calaminus, J. Engert, P. Kaatsch, H. Gadner, J.P.M. Bökkerink, R.J. Haas, K. Waag, M.E.G .Blohm, S. Dippert, C. Teske, D. Harms. Med Pediatr Oncol 1998; 31:8-15. N.M. Marina, B. Cushing, R. Giller, L .Cohen, S.J. Lauer, A. Ablin, R. Weetman, J. Cullen, P. Rogers, C. Vinocur, C. Stolar, F. Rescorla, E. Hawkins, S. Heifetz, P.V. Rao, M. Krailo, R.P. Castleberry. Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: a pediatric oncology group/children's cancer group intergroup study. J Clin Oncol 1999; 17:2137-2143. R.M. Freedmon, K.J. Lee, C. MacDonald, G. Taylor. Selected aspects of cardiac tumors in infancy and childhood. Pediatr Cardiol 2000; 21:299-316. S. Pipitone, M. Mongiovì, R. Grillo, S. Gagliano, V. Sperandeo. Cardiac rhabdomyoma in intrauterine life: clinical features and natural history. A case series and review of published reports. Ital Heart J 2002; 3:48-52. M. Tollens, D. Garb, D. Lang, J. Hess, R. Oberhoffer. Pericardial teratoma: prenatal diagnosis and course. Fetal Diagn Ther 2003; 18:432-436. A. Heerema-McKenney, M.R. Harrison, B.Bratton, J. Farrell, C. Zaloudek. Congenital teratoma. A clinicopathologic study of 22 fetal and neonatal tumors. Am J Surg Pathol 2005; 29(1):29-38. J.W. Pratt, D.M. Cohen, K.H. Mutabagani, J.T. Davis, J.J. Wheller. Neonatal intrapericardial teratomas: clinical and surgical considerations. Cardio Young 2000; 10:27-31. N. Roy, D.J. Blurton, A. Azakie, T.R. Karl. Immature intrapericardial teratoma in a newborn with elevated alpha-fetoprotein. Ann Thorac Surg 2004; 78(1):e6-38.