Germ Cell, Mesenchymal, and Thymic Tumors of the Mediastinum By Deborah F. Billmire Philadelphia, Pennsylvania Germ cell, mesenchymal, and thymic tumors of the mediastinum are an uncommon and heterogeneous group of neoplasms. Together they account for less than 25% of mediastinal tumors in childhood. The majority of these tumors are found in the anterior and superior mediastinum, but germ cell tumors and mesenchymal tumors may be located in all compartments. They share a broad range of histological subtypes and clinical behavior, tendency to be large in size, and a requirement for complete surgical excision as the major requirement for successful therapy. Copyright © 1999 by W.B. Saunders Company
HIS UNUSUAL SUBSET of mediastinal tumors may be found in any location within the mediastinum. Although germ cell, mesenchymal, and thymic tumors are defined by histological characteristics, there is a broad variation in presentation, therapy, and outcome within each subgroup.
GERM CELL TUMORS
Germ cell tumors are the third most common neoplasm of the mediastinum after lymphoma and neurogenic tumors. They account for 6% to 18%1-4 of mediastinal tumors in children and most often arise in the anterior mediastinum with an origin in or near the thymus gland. A small subset with distinctive clinical features has an intrapericardial location with origin from the ascending aorta, and rare cases arising in the posterior mediastinum also have been seen. Germ cell tumors are an interesting and very heterogeneous group of neoplasms that are believed to arise from primitive totipotential cells derived from an early event in embryogenesis. They may be found in many locations, particularly in the midline and para-axial sites. The mediastinum is the third most common site of origin for germ cell tumors and accounts for 7% of these tumors overall. The totipotential nature of the cell of origin allows for great diversity in type and degree of differentiation of the neoplastic cell. The tumors range from homogeneous masses of primitive embryonal tissues to well-differentiated teratomas. The potential p athways for differentiation are outlined in Fig 1. Germ cell tumors may contain any or all of the cell types listed. Overall, 86% of mediastinal germ cell tumors are benign. 5 Most of the malignant tumors are mixed tumors containing some element of teratoma as well as malignant components. A teratoma is a germ cell tumor that contains tissues derived from all three germ layers: endoderm, mesoderm, and ectoderm. The elements derived from each germ layer may be Seminars in Pediatric Surgery, Vol 8. No 2 (May). 1999: pp 85-91
immature or well differentiated. The variety of tissues present provides the opportunity for considerable complexity in the gross characteristics of the mass. Cystic areas frequently are seen because of enclosed areas of secretory epithelium, and calcification may be present because of attempted bone formation. Most germ cell tumors are fairly large with size ranging from 6 to 16 cm. The lack ofrestrictive boundaries to the mediastinum has been proposed as a permissive factor that allows significant growth before these tumors are discovered. 7 These large heterogeneous tumors with combinations of benign and malignant elements may be misdiagnosed when incisional biopsies are performed and if the tumor is not adequately sectioned during pathological examination. Assessment of the response to chemotherapy for malignant tumors also will be affected by the presence of benign components of the tumor that are not chemosensitive. The clinical behavior of immature mediastinal teratomas appears to be age dependent. In children under 15 years of age, excision is curative. Older children are prone to recurrence and aggressive disease progression. 8 The malignant elements of seminoma, dysgerminoma, and embryonal carcinoma must be recognized by their histological features and have no associated serum markers that can be followed. Malignant tumors that have followed the differentiation pathway to extraembryonic structures, however; secrete characteristic proteins, which may be detected in the serum. These protein markers may aid in recognition of the tumor type and provide a useful indicator of success or relapse with chemotherapy. Tumors with yolk sac (also called endodermal sinus) elements secrete the marker alpha-fetoprotein (AFP) , which has an in vivo half-life of 4 days. This protein also is produced in significant amounts by the normal fetal liver and yolk sac resulting in higher levels for healthy newborns than in older children. Interpretation of AFP levels in the first year of life is facilitated by the graph depicting the normal range for healthy infants developed by Tsuchida et al 9 (Fig 2). Tumors with elements of choriocarcinoma secrete the glycoprotein beta human chorionic gonadotrophin (B-HCG). This is a hormone From the Department of Surgery, Allegheny University of the Health Sciences, Sf Christophers Hospitalfor Children, Philadelphia, PA. Address reprint requests to Deborah F. Billmire, MD, Department of Surgery, Allegheny University of Health Sciences, St Christopher s Hospital for Children, Front St and Erie Ave, Philadelphia, PA 19134. Copyright © 1999 by WB. Saunders Company 1055-8586/99/0802-0007$ 10.00/0 85
DEBORAH F. BILLMIRE
EMBRYONIC ECTODERM. MESOOERM.ENDODERM
Fig 1. Histogenetic relationship of the various tumors derived from the primitive germ cell (from Grosfeld and Billmire,5 modified after Teilum et al"'. (Reprinted with permission."'
normally produced by the placenta and has an in vivo half-life of 2 to 3 days. Levels throughout infancy and childhood are quite low in the absence of malignancy. Presentation
The symptoms that lead to the diagnosis of mediastinal germ cell tumor are nonspecific but somewhat age dependent. Most children have a subacute course with symptoms ranging from several days to several weeks. These tumors may occur at any age but tend to be clustered in infancy and after puberty. Infants usually have respiratory symptoms including tachypnea and wheezing. Diminished breath sounds may be noted on one side of the chest if the tumor is eccentric with preferential extension into one hemithorax. The clinical picture may mimic or be accompanied by pneumonia caused by associated bronchial compression. Neonates 1,000,000
that present with congestive heart failure are a special subgroup that should raise the index of suspicion for the rare intrapericardial teratoma. lO •11 These patients almost always have pericardial effusion with some element of tamponade. Echocardiogram shows rotation as well as displacement of the heart caused by the intimate association of the tumor with the ascending aorta. 12 Older children may also present with respiratory complaints but more often will complain of chest pain. Signs and symptoms of superior vena cava syndrome also may be seen. Other unusual presentations of mediastinal germ cell tumors have included rupture into the pleural space with the acute onset of respiratory distress and rupture into the bronchus with expectoration of hair.13 Functioning ectopic tissue in the well-differentiated teratomas has produced massive hemoptysis from erosion of ulcerated ectopic gastric mucosal 4 and hypoglycemia from ectopic pancreatic islet tissue. 15 Precocious puberty may be seen in boys with germ cell tumors that secrete B-HCG. This combination of findings also should raise the suspicion of Klinefelter's Syndrome. Klinefelter's Syndrome is seen in up to 20% of boys with nonseminatous germ cell tumors of the mediastinum. 16 Chest radiographs will show the presence of a mediastinal mass, which is usually in the anterior and superior mediastinum. There may be bulging extension into one or both hemithoraces. A small number of mediastinal germ cell tumors originate in the posterior mediastinumY Calcification is seen in 35% of mediastinal germ cell tumors. 18 Computerized axial tomographic (CAT) scan is helpful to further define the mass and its relationship to surrounding structures. The finding of a complex mass with cystic and solid areas accompanied by irregular calcifications is highly suggestive of germ cell tumor. The cystic areas usually have a relatively thick wall, which differs from that seen with cystic hygroma and thymic or pericardial cysts.
Il"'r-t-,.. 11111 30
120 150 180 210 240 270 300 AGE IN DAYS
Fig 2. Normal range for AFP in the first year of life. 95% prediction band enclosed by curves. (Reprinted with permission.·'
The surgical approach to mediastinal germ cell tumors varies depending on the tumor size and location. As with all other tumors in the anterior mediastinum, consideration should be given to the risk of airway and great vessel compression. It is not unusual for infants to require intubation for respiratory distress at the time of presentation. Despite the large size of many of these tumors, difficulties with anesthetic induction are rare. Malignant tumors with evidence of local invasion and metastatic spread have occasionally been subjected to initial imageguided percutaneous biopsy under sedation. Caution must be used in the interpretation of this limited sample from such a heterogeneous tumor. In these situations, the finding of elevation in the tumor markers AFP or B-HCG will be helpful in confirming the suspicion of malignancy.
GERM CELL, MESENCHYMAL, AND THYMIC TUMORS
Surgical resection of the tumor is an essential component of therapy. Benign tumors are treated by excision only and often have a good plane of dissection in spite of their large size. 7 If left untreated, the natural history of benign teratomas is death from compression of vital structures. 7 Malignant tumors also should be resected at diagnosis if possible. The finding of adherence to local structures, especially pericardium and phrenic nerve, is common in these cases. Platinum-based chemotherapy regimens combined with bleomycin and etoposide are currently used with survival rates of 55% to 70%.19 Tumors that are unresectable at diagnosis may be explored after induction chemotherapy. In many cases, a large mass may persist even if the tumor markers have returned to the normal range. This may not indicate a treatment failure because many of these tumors are heterogeneous with large areas of benign tissue (Fig 3). Benign areas that are cystic may actually enlarge during therapy, a phenomenon that has long been recognized as the "growing teratoma syndrome."20 All children deserve a reexploration for potential resection and rebiopsy when a mass effect persists after chemotherapy. 21 MESENCHYMAL TUMORS
Mesenchyme is the embryonic connective tissue derived from the mesodermal layer of the trilaminar embryo.22 It provides the cell of origin for supporting structures such as fibrous tissue and fat, muscle, cartilage, bone, lymphatic tissue, and blood vessels. Cystic hygroma, lymphangioma, and hemangioma are an important subgroup that will be discussed in a separate chapter. The remaining mesenchymal tumors are all rare and account for only 5% of mediastinal tumors in collected series. I -4 Most information is available as isolated case reports or small reviews with limited follow-up data. Mesenchymal Tumors of Fat Cell Origin
This subgroup includes lipoma, lipoblastoma, and liposarcoma. Lipomas may occur at any age and are soft, slow-growing tumors that often are asymptomatic. If symptoms are present, they usually are secondary to local pressure with cough, chest pain, or dysphagia. 23 ,24 Some lipomas originate within the thymus gland and are called thymolipomas. Other sites of origin include the anterior or superior mediastinum and the posterior mediastinum within the wall of the esophagus. Lipomas are not calcified and have uniform low density on computerized axial tomography (CAT) scan. They should be treated by total excision and have a low recurrence rate. Lipoblastoma is a tumor of infancy. Most cases occur within the first year of life, and the tumor is rarely seen after 3 years of age. 25 It is more common in boys and may be well circumscribed or multicentric. Histologically, these tumors are composed of embryonal fat and have a promi-
nent vascular network. Lipoblastoma may be locally invasive and is prone to local recurrence but does not metastasize. The treatment is complete excision with prolonged follow-up. Liposarcoma is a rare tumor of childhood. Only 11 % of liposarcomas in children originate in the mediastinum. 26 It may occur at any age with infants and adolescents accounting for most cases. Most tumors are a myxoid variant but a variety of histological subtypes may be seen. The tumor may arise within the thymus gland27 or in other areas of the mediastinum. Most patients are asymptomatic but chest pain and respiratory complaints may occur. Liposarcomas are low density by CAT scan, but areas of necrosis and calcification sometimes are found (Fig 4). Local recurrence is common after excision, and distant metastasis to lung and liver may occur. Radiation and chemotherapy (vincristine, dactinomycin, cyclophosphamide) have been used with variable results. Mesenchymal Tumors of Muscle Cell Origin
This subgroup of tumors includes leiomyoma, rhabdomyosarcoma, extraosseous Ewings, epithelioid sarcoma, and undifferentiated sarcoma. 28 The tumors may arise in any compartment of the mediastinum. 29 Pleura and diaphragm frequently are the site of origin. Mediastinal sarcomas may be seen at all ages in childhood, and most patients are symptomatic at presentation. In addition to the more common complaints of pain and respiratory difficulties, hemoptysis also has been reported. 3o On CAT scan, these are large soft tissue masses. Epithelioid sarcoma may show calcification or bone formation. 30 Surgical resection is the cornerstone of therapy for these tumors. Difficulties in complete resection frequently are noted because of invasion of critical neighboring structures. Procedures that include sacrifice of lung, superior vena cava, pericardium, and vertebra have been reported to achieve this goal,29 The accuracy of margin status also may pose a challenge because these tumors may extend along pleural surfaces without clear boundaries. In a recent review by Andrassy et al,31 the local recurrence rate of group I patients (complete resection) was higher than that for group II patients (microscopic residual). Most group I patients did not receive any further therapy, but nearly all group II patients received local radiation therapy. It was suggested that the determination of true margin status could be difficult and posed problems with accurate staging. Overall survival rate was better for localized disease, but local recurrence was common. The critical location of these tumors may cause mortality from local recurrence even without distant metastases. Multimodal therapy including radiation and chemotherapy are required with emphasis on complete surgical excision whenever possible.
DEBORAH F. BILLMIRE
Fig 3. A 16-month-old girl presented with 2-week history of fever and respiratory symptoms (A,BI. AFP was markedly elevated, and biopsy result of a lung metastasis ICI confirmed yolk sac histology. Chemotherapy produced tumor shrinkage and normalization of AFP after four cycles (D,EI. Despite continued therapy, the large remaining mass remained stable and was resected after two additional cycles. Histology results showed only residual benign teratomatous elements. (Photos courtesy Barbara Cushing, MD.I
GERM CELL, MESENCHYMAL, AND THYMIC TUMORS
Thymoma and Thymic Carcinoma
Fig 4. CAT scan of a 15-year-old girl with liposarcoma involving the posterior mediastinum with tran~dlaphragmatic extension to the abdomen. Adherence to the inferior vena cava is evident, and calcified area may be seen in the low-density tumor.
Mesenchymal Tumors of Cartilage Cell Origin
Extraskeletal chondrosarcoma has been reported in the posterior mediastinum in children during the second decade of life. 32 These tumors present with pain. CAT scan shows a soft tissue mass with punctate calcification that may be confused with neuroblastoma. Despite adherence to surrounding structures, a plane of dissection may be achieved, allowing complete resection. Of two children treated by excision only, one was well at 6-year follow-up, and one had local recurrence. THYMIC TUMORS
The thymus develops during the sixth week of gestation from paired primordia in the ventral portion of the third pharyngeal pouch. Over the next 3 to 4 weeks, there is a migratory descent into the thorax, which follows a path from the pyriform sinus, through the thyrohyoid membrane, between the carotid artery and vagus nerve to lie in the anterior mediastinum at the level of the aortic arch. 33,34 The endodermal derivative has a primitive lumen (the thymopharyngeal duct), which becomes obliterated during development. There also is an ingrowth of lymphocytes from the surrounding mesenchyme that contributes to the formation of the thymic lobules. Thus, there are two primary cell types within the thymus that can give rise to neoplasia: epithelial cells and lymphocytes. The supporting mesenchyme of the thymus also may give rise to various neoplasms, but these will be discussed separately. The finding of germ cell tumors arising in the thymus is presumed to be because of migration of totipotential cells into the thymus during early development and will be discussed with other germ cell tumors of the mediastinum. Primary tumors and cysts of the thymus may be found anywhere along the embryological pathway of descent of the thymus gland and frequently involve the neck as well as the mediastinum.
These are rare neoplasms derived from the epithelial and lymphoid components of the thymus. The behavior of thymic tumors in children is not well understood because of the rare incidence, the variable morphology that often requires special stains and electron microscopy for accurate diagnosis, and the broad spectrum of clinical behavior. Overall, there have been less than 50 primary thymic epithelial neoplasms reported in childhood.35 Thymic carcinoma is defined by the overt recognition of malignant features by cytological examination including cytological atypia and mitotic index. The most common malignant patterns are anaplastic tumors or small cell carcinomas with neuroendocrine features. This is in contrast to adults that usually exhibit well-differentiated squamous or lymphoepithelial carcinoma. 36 Pediatric thymic carcinomas are aggressive malignancies that usually cause chest pain and shortness of breath. Local invasion of surrounding structures with metastases to lung, liver, and bone are common at diagnosis. Death within 6 months of presentation frequently is seen. 37 ,38 Thymomas are a varied spectrum of primary thymic tumors with bland cytological features and no overt histological evidence of malignancy.39 In spite of the innocent histological picture, their clinical behavior ranges from a well-encapsulated focal lesion that is cured by simple excision to a pattern of local invasion and metastatic spread with eventual death. In a large review of thymoma in adults from the Mayo Clinic, 32% had evidence of local invasion and 6% had metastasis at diagnosis. There was a local recurrence rate of 15% in patients who had undergone complete surgical resection, and the 5-year survival rate was 67%.39 Data on pediatric patients with thymoma is limited, but similar clinical behavior ranging from successful primary resection to multiple recurrences and death have been reported. 35,40,41 Presentation of thymic tumors ranges from asymptomatic discovery on chest x-ray to chest pain and shortness of breath. Superior vena cava syndrome may occur, and pericardial and pleural effusions often are noted with malignant lesions. CAT scan demonstrates an anterior mediastinal mass that may be solid or mixed with cystic and solid components. 40 Calcification has been described in 2% to 25% of cases. 40 ,42 For all thymic neoplasms, surgery is the mainstay of therapy. Complete resection including contiguous structures if necessary should be the goal. 38 ,42 For malignant lesions, postoperative chemotherapy and radiation have been used with limited success. Thymic Cysts
Thymic cysts are benign tumors that are believed to originate from remnants of the thymopharyngeal duct. An
DEBORAH F. BILLMIRE
alternative explanation is that the cyst is a consequence of degeneration in Hassall's corpuscles. They may be unilocular or multilocular and contain clear fluid. Most are asymptomatic, but hemorrhage into the cyst cavity with enlargement may produce tracheal compression and acute respiratory distress. 34 The cyst may be localized entirely in the mediastinum or in the neck but frequently includes both sites. Thymic cysts should be treated by surgical excision to prevent complications of local expansion and to confirm the histology. Other thymic lesions, which may have a cystic appearance, include nodular sclerosing Hodgkin's disease,4o seminoma, and cystic teratoma,43 Cervical lesions with mediastinal extension (Fig 5) often can be excised through a transverse cervical incision. 44 Contained mediastinal cysts may be approached by either median sternotomy or thoracotomy depending on their size and location. A recurrence rate of 2% has been reported for thymic cysts in adults, but this has not been seen in children. 34 Myasthenia Gravis and the Thymus
The relationship between myasthenia gravis and abnormalities of the thymus has long been recognized in adults. Overall, approximately 82% of adults with myasthenia gravis have an abnormality of the thymus gland, and 15% have a thymoma. 42 Other autoimmune disorders that have been associated with thymoma in adults include inflammatory bowel disease, collagen vascular disease, hypogamma globulinemia, and hypoplastic or aplastic anemia. In childhood, abnormalities of the thymus usually are an isolated phenomenon, but occasional links to other disorders have been noted. In 1985, Furman et al45 reported on a 4-year-old girl with respiratory symptoms from a large thymoma. She also had evidence of muscle weakness by history. Postoperatively she had florid symptoms of myasthenia gravis with a positive edrophonium (Tensilon) test result and required 7 days of mechanical ventilation. They were able to find only five other cases of myasthenia gravis associated with thymoma in childhood. Youssef46 reported eight children with myasthenia gravis who underwent thymectomy for significant symptoms. None had thymoma, but four had lymphoid hyperplasia. Six of the patients had dramatic improvement with complete recovery at 3 to 11 years of follow-up. He emphasized the importance of "radical" thymectomy, which is achieved by median sternotomy
Fig 5. A 4-year-old girl presented with a large neck mass extending deep into the anterior mediastinum by CAT scan. A multiloculated thymic cyst was excised through a transverse cervical incision without difficulty.
with removal of the thymus and all fatty tissue of the mediastinum from the diaphragm to the pharynx. Thymoma also has been seen in association with aplastic anemia in a child. 47 Human Immunodeficiency Virus and the Thymus
Approximately 2% of human immunodeficiency virus (HlV)-infected patients in the United States are in the pediatric age group.48 These children are at increased risk of malignancy as well as unusual infections caused by their immune compromised state. A recent disease entity involving the thymus has been described in these children. Eight of the 440 pediatric HIV patients followed up by the pediatric branch of the National Cancer Institute were noted to have an asymptomatic anterior mediastinal mass on routine chest x-ray.49 CAT scan showed a multiseptated cystic mass of the thymus with characteristic features in all patients. Five of the eight patients also had lymphoid interstitial pneumonitis. Five children had open wedge biopsy, and one had complete resection of the mass. Histological examination showed distorted architecture with follicular hyperplasia and cysts but no evidence of malignancy. The mass resolved in two patients and decreased in three of the others. They recommended careful observation with serial CAT scans in children with HIV who demonstrate the typical CAT scan findings of multi septate cystic lesions of the thymus as long as there are no signs of malignancy and no clinical symptoms that may be attributed to the mass.
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GERM CELL, MESENCHYMAL, AND THYMIC TUMORS
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