Koushan Siami-Namini, M.D., Jian T. Yang, M.D. Ph.D., Rosemary E. Zuna, M.D., Kar-Ming Fung, M.D., Ph.D. Last update: October 30, 2003.

Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Clinical information:

    The patient was an 18 year-old man who presented with chest pain and shortness of breath. The pain would last for seconds followed by spontaneous resolution. There was no history of cough, hemoptysis, fever, or chills. A chest x-ray revealed fullness of mediastinum. CT scan revealed a 7.5 x 6.2 x 9.1 cm mass that extended inferiorly along the left superior aspect of the heart. The mass encroached the main pulmonary trunk. Remnant of tissue consistent with residual thymus were noted. The lung was well areated and free of nodules or consolidation. A CT guided fine needle aspiration (FNA) was performed.

   A surgery was performed and yielded a 9.5 x 6.5 x 5.5 cm encapsulated mass with attached soft tissue that appeared to be thymic tissue on subsequent  microscopic examination. The mass had a gray-yellow, solid cut surface with multifocal hemorrhage and necrosis. The capsule was largely intact with no macroscopic evidence of penetration identified. 

Pathology of the case: 

A. DiffQuick	B. DiffQuick	C. DiffQuick	D. PAP stain	E. PAP stain

F.	G.	H.	I.	J.	K.
L.	M. PAS	N. a-fetal protein	O. a1-antitrypsin

Cytopathology of CT guided FNA specimen:

    The fine needle aspiration (FNA) specimen (Panel A, B, C, D, and E) contain clusters of loosely packed cohesive cells without associated lymphoid cells or tigroid background. Some of the cell clusters (Panel A) appear bland but other cells are highly pleomorphic (Panel B, D, and E). The bland appearing cells may represent reactive mesothelial cells and the highly pleomorphic cells are tumor cells. The tumor cells have an epithelioid appearance with large nuclei and moderate amount of cytoplasm. While nucleoli are not prominent in the sections stained by DiffQuick  (Panel A and B) , large nucleoli are noted in sections stained by Papanicolaou stain  (Panel C, D, and E).  Small clumps of acellular hyaline material are present and their metachromatic property is best demonstrate in the DiffQuick stained sections  (Panel C). These material appears as bluish green substance on sections stained by Papanicolaou stain. These hyaline material provides good clue for the cytologic diagnosis of a mediastinal yolk sac tumor and have been described by Yang et al. ^{19, 20}. They correspond to the hyalinized eosinophilic globules in yolk sac tumors. Based on these cytologic features, a diagnosis of germ cell tumor with yolk sac tumor component was made.

Gross pathology:

    The surgically excised specimen is an encapsulated mass (9.5 x 6.5 x 5.5 cm) attached to a portion of thymus (6.5 x 4.0 x 1.0 cm). The capsule of the mass is 0.1 to 0.3 cm in thickness, smooth and grossly intact. The mass has a gray-brown, and soft cut surface with multifocal hemorrhage. The mass is well contained and dose not invade into surrounding mediastinal structures.  The thymus has a tan-yellow, lobulated cut surface withougt any gross abnormality. 

Histopathology of surgical specimen:

    A survey at low-magnification shows a necrotic neoplasm (Panel F). The tumor cells arrange in different patterns. The tumor cells are densely packed in some areas but loosely packed in other areas.  At medium-magnification, several different patterns of architecture are disclosed. The most commonly encountered pattern in this case is a reticular-microcystic arrangement of cells (Panel G). In a significant amount of other areas, there are hypocellular to myxoid non-neoplastic stroma lined by a single layer of neoplastic cells (Panel H, I). The tumor cells have moderate to large nuclei with substantial pleomorphism. The chromatin is clumpy and hyperchromatic (Panel J). In some areas the tumor cells has an hepatoid appearance featured by a smaller nuclei with substantial amount of amphophilic cytoplasm (Panel K). Schiller-Duval bodies are occasionally noted (Panel L). A variable number of eosinophilic globules are also present and they are strongly positive for periodic acid-schiff (PAS) reaction (Panel M). Results of immunohistochemistry are as follows:

Comment:

    Yolk sac tumor arising in the thymus often have extensive invasion into the adjacent tissue. In this cases, the tumor is still confined. The histology is quite typical for a yolk-sac (endodermal sinus) tumor. The reticular-microcystic pattern being illustrated here is the most common pattern being encountered.  Only a small number of Schiller-Duval bodies are present. The large cells with hepatoid look correspond to the hepatoid pattern in yolk sac tumor. The solidly arranged sheets of tumor raise the possibility of an embryonal carcinoma. However, the nuclear pleomorphism, although significant, is still short of that from embryonal carcinoma. The extracellular, PAS(+), eosinophilic hyaline globules are also typical for yolk sac tumor. These globules are often immunoreactive for a-fetal protein and a-1-antitrypsin. In our case, they are only positive for a-1-antitrypsin. The lack of CD30 immunoreactivity, again, does not support a diagnosis of embryonal carcinoma.

Discussion: General Information  Embryonic Consideration  Pathology  Differential diagnosis  Cytogenetics

General Information   

    Yolk sac tumor, also known as endodermal sinus tumor, belongs to the family of germ cell tumor. Gonadal and extragonadal germ cell tumors derive from germ cells and they have very diversified phenotypic features. Differentiation of germ cell tumors can be separated into two major groups: tumor with teratomatous differentiation and non-teratomatous differentiation. Teratomatous differentiation can be composed of mature and/or immature tissue. Within the non-teratomatous differentiation, there are two major subtypes: tumor with seminomatous differentiation resembling primordial germ cells (seminoma and dysgerminoma) and non-seminomatous differentiation. The non-seminomatous differentiation occur in the form of undifferentiated component (embryonal carcinoma) or extraembryonic differentiation (yolk sac tumor and choriocarcinoma). All the aforementioned types of differentiations can occur as pure or combined form that lead to a rich diversity in histopathologic features. Gonadal and extragonadal germ cell tumors are essentially identical in phenotypic features. However, the relative incidence of different subtypes varies greatly in different anatomical locations and organs. Moran and Suster provided a useful classification of germ-cell tumor of the mediastinum ¹. Interested readers should refer to the comprehensive articles by Moran et al. ^{1, 2, 3}.

    Primary germ cell tumor is an uncommon tumor of the mediastinum and account for 10-15% of all mediastinal tumors ⁴. Primary germ cell tumor of the mediastinum occurs most often in young adults in the 2^nd to 4^th decade ^{5, 6} but can also occur in the very young and elderly ^{1, 7}. Although mediastinal teratomas are as common in males and females, non-teratomatous mediastinal germ cell tumors occur almost exclusively in male ^{5, 1}. Rare cases have been described in female patients ⁸.

    Some of the mediastinal germ cell tumors remain asymptomatic and are found as incidental findings. Those tumors that manifest produce symptoms and signs resulted from compression or invasion of local structures such as compression of the vena cava. Symptoms are non-specific. The most common ones include chest pain, shortness of breath, weight loss, chills and fever, superior vena cava syndrome. Trichophysis (coughing up of hair), however, is a rare but diagnostic feature of teratomas. Association of Kleinfelter’s syndrome ⁹, sexual precocity ¹⁰ and hematologic malignancies ¹¹ with mediastinal germ cell tumors have also been reported. An increased serum level of a-fetal protein and human chorionic gonadotrophin suggest the presence of non-seminomatous component.

    Among non-semionomatous-non-teratomatous germ cell tumors of the mediastinum, yolk sac tumor is the most common ³.  Mediastinal yolk sac tumor was first described by Teilman ¹² and comprises more than half of all the cases in the series by Moran et al. The second most common entity is combined germ cell tumor that comprises about one-fifth of all cases. Choriocarcinoma and embryonal carcinoma are less common and each comprises about one-tenth of all cases with embryonal cell carcinoma as the least common one ³. The diagnosis of primary choriocarcinoma in the mediastinum can be contraversial due to the highly metastatic nature of choriocarcinoma.

    For treatment and prognostic purposes, mediastinal germ cell tumors are divided into seminomatous and non-semintomatous group. A tumor should be treated as non-seminomatous type if it contains both seminoatous and non-seminomatous components. The long-term survival with treatment in mediastinal seminomas can reach 85%-90% ^{13, 14} largely due to its radiosensitivity and also 75% of these tumors are stage I disease at presentation ¹. The non-seminomatous mediastinal germ cell tumors carry worse prognosis than its gonadal counterparts ^{1, 3, 14} or retroperitoneal primary germ cell tumors ¹⁵. A 5-year survival of 45% in patients with mediastinal non-seminomatous-non-teratomatous mediastinal germ cell tumor has been achieved in one study ¹⁵. Yolk sac tumors appear to have worse prognosis ¹⁶ and choriocarcinoma is uniformly fatal ¹.

Embryonic considerations

    With their embryonic origin, it would not be surprised to see that germ cell tumors occur most often in the gonads. However, they are also seen in other midline locations such as the pineal gland, sellar-suprasellar region, retroperitoneum, mediastinum and sacrococcygeal region ¹⁷. During the 4^th to 6^th week of embryonic development, the primordial germ cells migrate from their original midline location near the origin of the allantois to the gonadal ridge of the future gonads ¹⁸ along the dorsal mesentery of the hindgut. This process partly explained the occurrence of germ cell tumor along the midline. It is well known that the primordial germ cells disseminate widely throughout many tissues and organ during early embryonic development. The extragonadal primordial germ cells persist most frequently in the mediastinum and the diencephalopineal region. The reason for this distribution remains uncertain. This distribution, however, partly explains the relatively high frequency of extragonadal germ cell tumor in the mediastinum and pineal region relative to other midline locations.

Pathology    

    Mediastinal non-teratomatous germ cell tumor almost always presents as an anterior mediastinal mass ³. Macroscopically, mediastinal germ cell tumor is a large and soft mass with the size of ranging from 6 to 20 cm in greatest dimension. The cut surface is homogeneous, freshy, and decorated by areas of hemorrhage and necrosis. They are unencapsulated and have inconspicuous boundary. Invasion of the surrounding mediastinal structures is a frequent intraoperative finding. In uncommon cases, mediastinal seminoma may be accompanied by extensive fibrosis. Histologically, mediastinal germ cell tumors have features similar, if not identical, to their gonadal counterparts. Here, we will restrict our discussion to yolk sac tumors.

    Yolk sac tumors exhibit a wide range of histologic patterns that differ considerably from each other. In most cases, a mixed histologic pattern is present and, not infrequently, one or two patterns may predominate. The most common pattern is the microcystic-reticular pattern. The other histologic patterns included endodermal sinus, solid, alveolar-glandular, polyvesicular vitelline, myxomatous, macrocystic, papillary, intestinal, hepatoid, and spindle cell. Although there is a rich variation in architecture, the variations in cytologic features are less impressive. The tumor cells are medium to large and have clear to pale, granular cytoplasm. Hobnail cells are not uncommon and often seen with the papillary pattern. The nuclei are large, vesicular, and contain prominent nucleoli. Yolk sac tumors are mitotically active. Necrosis and hemorrhage are common.

    Yolk sac tumor often, but not always, contains bright, eosinophilic globules. These extracellular, small, round, brightly eosinophilic, hyaline, strongly PAS-positive, diastase-resistant globules or droplets are most often associated with the microcystic-reticular pattern and endodermal sinus pattern. These globules are considered to be secreted by the tumor cells and accumulate within the cytoplasm. As the amount of secretion increases, the cell become distended and ruptures, discharging its contents into the surrounding tissue. Although characteristic, these eosinophilc hyaline globules are not diagnostic of yolk sac tumor because they are also found in other malignant tumors particularly those with poor differentiation. When they are present in specimen from fine needle aspiration, as in our case, they are metachromatic and provide a good clue for diagnosis ^{19, 20}.

    The microcystic-reticular pattern is characterized by a loose vacuolated network with small cystic spaces or microcysts that give rise to a meshwork of communicating space. The microcysts are lined by flat, pleomorphic, epithelium-like cells with large hyperchromatic or vesicular nuclei. The myxomatous pattern is similar to the microcystic pattern but is loosely packed and contains mucoid material.

    The papillary or "festoon" pattern is composed of papillary structures featured by fine fibrovascular cores lined by mitotically active epithelium-like cells with considerable degree of cellular and nuclear polymorphism. The connective tissue may show extensive hyalinization.

    The endodermal sinus pattern is composed of perivascular formations featured by a narrow band of connective tissue with a capillary blood vessel in the center and lined by a layer of cuboidal or low columnar embryonal epithelial-like cells. The cells have large, slightly vesicular nuclei, prominent nucleoli. A single layer of flat cells lines the surrounding sinusoidal space. These characteristic perivascular formations, the Schiller-Duval bodies, are considered diagnostic of yolk sac tumor but they are not always present. Embryologically, the downgrowth of yolk sac epithelium into the extraembryonic mesenchyme of the placenta in rodent is known as endodermal sinuses. The Schiller-Duval bodies are similar to the endodermal sinus of placenta in rodent that was first described by Duval in 1891 ²¹. The loose myxomatous pattern was considered to be analogous to magma reticulare or the extraembryonic mesoderm of the exocelom. Teilum also demonstrated that the reticular and papillary patterns recapitulate the labyrinthine placenta of the rodents ^{22, 23}. Recognition of Schiller-Duval bodies in fine needle aspiration, although not a common event, provide good clue for diagnosis ^{19, 20}.

    The alveolar-glandular pattern is composed of alveolar, gland-like, or larger cystic spaces and cavities lined by flat or cuboidal epithelium-like cells with large, prominent nuclei and surrounded by myxomatous stroma or cellular aggregates. The solid pattern is composed of aggregates of small epithelium-like polygonal cells with clear cytoplasm and large vesicular nuclei with prominent nucleoli. The polyvesicular vitelline pattern is composed of numerous cysts or vesicles surrounded by compact connective tissue stroma. The vesicles are lined partly by columnar or cuboidal epithelial cells, frequently showing basal or paraluminal vacuolation, and partly by flat mesothelium-like cells. The hepatoid pattern is composed of polygonal, epithelioid cells with eosinophilic, uniform, or granular cytoplasm and display histologic resemblance to hepatocytes. This pattern is uncommon but is focally present in our case under discussion. The spindle cell pattern is also an uncommon pattern ^{24, 25}. The granular or primitive endoderemal (intestinal) pattern is composed of nests or collections of primitive endodermal glands surrounded by connective tissue, which varies from loose and edematous to dense and hyalinized. The degree of differentiation varies from primitive to relatively well differentiated. The tumor may resemble a mucin-secreting adenocarcinoma. The intestinal pattern is associated with very high levels of a-fetal protein in serum.

Differential diagnosis

    Under most situations, the histopathologic features of yolk sac tumor of the mediastinum allow rapid recognition. The possibility of a metastatic yolk sac tumor must be ruled out before a diagnosis of primary tumor is made. The occasional predominance of large clear cells in solid or glandular arrangement would suggest a metastatic clear cell carcinoma. As yolk sac tumors tend to have mixed histology, a thorough search would often reveal evidence of yolk sac tumor. Immunohistochemical demonstration of a-fetal protein is a helpful tool. The age and clinical history are helpful. Local extension of a primary malignant tumor of the lung with extension into the mediastinum is also a possibility. In some clinical situations, it is not possible to distinguish a primary mediastinal tumor invading into the lung or the vice versa. Again, a thorough histologic search and immunohistochemistry are helpful.

    Embryonal carcinoma may pose diagnostic problems as it has one or more of the characteristics of yolk sac tumors. In general, embryonal carcinoma is solid or glandular in arrangement, has far more pleomorphism and necrosis than yolk sac tumors. In contrast, yolk sac tumor has clear cells, distinctive histologic arrangement, and hyaline bodies. Most embryonal cell carcinomas are positive for CD10. It should also be noted that a small number of yolk sac tumors are also positive for CD10.

    The rare hepatoid and intestinal pattern may suggest metastatic hepatocellular carcinoma or metastastatic adenocarcinoma. Again, careful search for the distinctive histologic features of yolk sac tumor as well as immunohistochemistry would be helpful in establishing the correct diagnosis. The spindle cell pattern may suggest sarcoma.

Cytogenetics and association with hematologic malignancies

    Isochromosome 12p has been demonstrated in gonadal and extragonadal germ cell tumors ^{27, 28} which often lead to a gain of sequences. The critical region involved in the pathogenesis of germ cell tumor appear to be located at chromosome 12p11.1-12p12.1 ²⁹ and the genes involved may be associated with suppression of apoptosis and Sertoli cell-independent of during progression from in situ to invasive testicular germ cell tumor ³⁰.

    Mediastinal germ cell tumor is associated with an increased incidence of hematologic malignancy with acute megakaryoblastic leukemia and malignant histiocytosis as the most common associated hematologic malignancy. In the study performed by Nichols et al. ¹¹, the median time between the diagnosis of mediastinal germ cell tumor and development of hemopoietic malignancies was approximately 5 months. It does not seem to be a result of cisplatin-based chemotherapy in patients with mediastinal germ cell tumor. This phenomenon is restricted in patients with non-seminomatous mediastinal germ cell tumors particularly those with histologic or serologic evidence of yolk sac tumors ^{11, 31, 32, 33}.  Isochromsome 12p, a rare genetic change in hematopoietic malignancies, has bee identified in the leukemic component of these cases ^{33, 34}. These findings suggest that the mediastinal germ cell tumor and simultaneously occurring hematopoietic malignancy may share the same precursor cells in the mediastinum. Interestingly, isochromosome 12p has also been identified in two cases of acute myeloid leukemia that does not have evidence of mediastinal germ cell tumor ³⁵. This further raises the question on the role of isochromosome 12p in the pathogenesis of mediastinal germ cell tumorand hemoatologic malignancies.

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