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Primary Anterior Mediastinal Tumors in Children and Adults
COLLECTIVE REVIEW
P h g y Anterior Mediastinal Tumors in dren and Adults Bradley Mullen, M.D., and J. David Richardson, M.D. ABSTRACT This review details pertinent anatomical, radiological, pathological, and clinical information regarding primary anterior mediastinal tumors. Although the majority of these lesions are included in one of several subgroups, for example, thymic tumors, teratomas, or thyroid abnormalities, other less common entities will occasionally be encountered by the practicing surgeon. Likewise, there are variations in the frequency distribution of anterior mediastinal lesions in children as opposed to adults. Management of these individual lesions is outlined. Primary anterior mediastinal tumors are uncommon clinical entities on which there are few systematic reports in the surgical literature. The majority of series report occurrence of mediastinal tumors in the anterior compartment. The anatomical boundaries of the mediastinum may be defined differently, thereby including or excluding tumors from the study. Although any anatomical division of the mediastinum is arbitrary, for the purposes of this review, the anterior compartment is defined as that area bounded by the sternum anteriorly, the heart posteriorly, the thoracic inlet superiorly, and the diaphragm below. Located in the anterior mediastinum are the thymus gland, the adipose, lymphatic, and areolar tissues, and the thyroid and parathyroid glands on occasion. The relative incidence of common primary anterior mediastinal tumors in a collected series of 702 adults is listed in Table 1, and the relative frequency of common lesions in 179 children is reported in Table 2. In only one series [l] was the anterior compartment not found to be the most common area from which the mediastinal tumors arose. The incidence of specific tumors differs slightly in the various series, although general tendencies are apparent, especially in adults. Thymic lesions are the most frequent in adults, and the vast majority are thymoma. Lymphoma is the second most common tumor, followed by endocrine and germ cell neoplasms (roughly equal in incidence). In children, lymphoma is the most common primary anterior mediastinal tumor. Germ cell neoplasms are the second most prevalent tumor, followed by thymic lesions and mesenchymal tumors. In children, thymic abnormalities consist primarily of hyperplasia and cysts; only 5 cases of thymoma have been reported [l, 21. No series involving either From the Department of Surgery, University of Louisville School of Medicine, Louisville, KY. Address reprint requests to Dr. Richardson, Department of Surgery, Ambulatory Care Building, University of Louisville, Louisville, KY 40292.
338 Ann Thorac Surg 42:338-345, Sep 1986
children or adults revealed a sex-linked predilection for these tumors, except for specific types of germ cell tumors known to occur virtually exclusively in the male sex.
Signs and Symptoms A variety of signs and symptoms ranging from those clearly nonspecific to those virtually pathognomonic may cause the patient with an anterior mediastinal tumor to be seen for evaluation. Although many lesions are found on routine chest roentgenograms, nearly twothirds of patients have specific symptoms [3]. The only exceptions seem to be in reports from military centers where large numbers of screening chest roentgenograms are made of healthy young people. The most common symptoms are chest pain, cough, and dyspnea caused by compression or invasion of contiguous structures. Chest pain usually signals the invasive spread of malignant neoplasia. Other less common symptoms include hemoptysis, dysphagia, hoarseness, Horner’s syndrome, vena caval obstruction, arrhythmias, fever, weakness, and weight loss. The presence of symptoms in a patient with an anterior mediastinal mass clearly has prognostic importance because malignant lesions are more often symptomatic than benign lesions [2, 31. For example, King and associates [2] observed that 23 (44%) of 52 patients with benign lesions were symptomatic, whereas 98 (72%) of 136 patients harboring malignancy complained of symptoms. Despite the tendency for malignant lesions to be more often symptomatic, the presence of symptomatology is not specific for malignancy. In the usual group of symptomatic patients, approximately half of the lesions will be benign and half, malignant [4]. Besides symptoms caused by compression and invasion, other signs and symptoms, such as endocrinological abnormalities, cardiovascular lesions, and associated systemic syndromes, frequently occur in association with anterior mediastinal tumors. Thymoma associated with myasthenia gravis (MG) is perhaps the classic example. Other examples are discussed in the sections dealing with the specific tumors. Collectively, an infant or child is more likely to have symptoms than an adult [l].Several reasons could account for this finding. 1. Children are more likely to have a malignancy than adults [5-71. 2. Because of the smaller size of the thoracic cavity in the child, any lesion is more likely to cause symptoms by compression or invasion. 3. The most common location of primary anterior medi-
339 Collective Review: Mullen and Richardson: Primary Anterior Mediastinal Tumors
Table 1. Relative Frequency of Common Primary Anterior Mediastinal Tumors in 702 Adults Study
Tumor
41
7
Thymic lesions Germ cell tumor
231 60 107 61
37 10 7 13
459 43
67 58
Lymphoma Endocrine tumor Total % of series
Incidence 38
60
Total
(%I
31 21 37 11
7 5 9 21
21 7 0 6
327 103 160 112
47 15 23 16
100 48
42 62
34 50
702
. . . . . .
59
...
Table 2. Relative Frequency of Common Primary Anterior Mediastinal Tumors in 179 Children Study
Incidence
Tumor
61
1
62
2
Total
(%)
Thymic lesion” Germ cell tumor
4 21 9 7
13 4 0 2
9 5 13 8
4 13 58 9
30 43 80 26
17 24 45 15
41 39
19 17
35 38
84 45
179
Lymphoma Mesenchymal tumorb Total % of series
...
”This includes thymic cyst, thymic hyperplasia, and thymoma bSee text for description of included tumors.
astinal tumors in children is near the trachea, which results in the high frequency of respiratory symptoms. In all patients with symptoms of respiratory distress, more than three-fourths were less than 2 years old, and nearly 80% of these infants had symptoms of tracheal compression.
Thymic Lesions Thymic lesions are the most common cause of a primary anterior mediastinal mass in adulthood, and the majority are either a benign or malignant thymoma. Though these thymic lesions are not common in childhood [8], cysts and hyperplasia represent the predominant pathological finding when tumor is confirmed. Thymoma is relatively unique among tumors because the prognosis appears to be more closely related to gross characteristics at operation than to histological appearance [9, 101. Indeed, degree of encapsulation and invasion of adjacent tissues define malignancy for these tumors rather than the histological appearance of the tumor cells [9, 111. Those tumors displaying cellular atypia and other characteristics usually considered as evidence of malignancy are included under the classification thymic carcinoma and are discussed later. Generally, thymoma is classified histologically into three types based on the predominant cell type: lymphocytic, epithelial, and lymphoepithelial (mixed). The tumor stage is determined by the extent of tumor invasion at
operation. Stage I disease is represented by intracapsular growth with the capsule remaining intact, and may be referred to as a benign thymoma. Stage I1 disease is indicated by growth into surrounding organs, particularly the mediastinal fat, pleura, or pericardium. Intrathoracic metastasis is classified as Stage I11 disease, whereas Stage IV lesions have extrathoracic metastasis. Remote metastases tend to occur in the liver, bone, and brain and are present in approximately one-quarter of patients with invasive thymoma who have operation (91. Typically, the patient with thymoma may be of either sex, will be in the fifth or sixth decade of life [8, 12-15] when the tumor is diagnosed, and will have a 50% chance of being asymptomatic [9,12,15] when the lesion is discovered on routine chest roentgenogram. Since the relationship between thymoma and MG was described in 1901 and Blalock and co-workers (161 reported the successful excision of a thymic cyst in a girl with MG, the association of thymoma and a variety of syndromes has been actively studied. Approximately 15% of patients with MG have thymoma [8], either benign or malignant, while 10 to 50% of patients with thymoma have MG. Other systemic syndromes occurring with thymoma include erythroid and neutrophil hypoplasia, pancytopenia, Cushing’s syndrome, DiGeorge syndrome, carcinoid syndrome, Lambert-Eaton syndrome, nephrotic syndrome, syndrome of inappropriate secretion of antidiuretic hormone, Whipple’s disease, lupus ery-
340 The Annals of Thoracic Surgery Vol 42 No 3 September 1986
thematosus, pemphigus, scleroderma, polymyositis, polyneuritis, polyarthropathy, myotonic dystrophy, Sjogren’s syndrome, Addison’s disease, hypogammaglobulinemia, and thyroid carcinoma [8, 91. Although an immune basis seems fairly clear, the exact etiology and pathogenesis linking these syndromes to the thymic abnormality remain to be clearly elucidated. Benign thymoma (Stage I) has an excellent prognosis with complete cure likely after total surgical excision. The recurrence rate following complete resection of benign thymoma is reported to be less than 2%. Five-year survival ranges from 80 to 100% for benign thymomas and from 23 to 54% for malignant thymomas. There are claims that thymoma patients with MG have a worse prognosis than those without it [ll], but this issue is far from settled. Shamji and associates [15] presented data demonstrating that MG apparently augments survival in affected patients. They believed the improved survival reflected improved long-term medical management of MG . In treating thymoma, aggressive surgical staging and total excision should be attempted [8, 91. Thymomas, even though extensive when first seen, must be considered to be adherent to and compressing adjacent structures rather than truly invasive. Although contiguous structures may need to be resected along with the tumor, in most instances, thymoma can be completely removed once the proper plane of dissection is established [8]. Complementary irradiation is required for Stage I1 or 111 lesions [8, 9, 111, and patients with Stage IV tumors may require irradiation and systemic chemotherapy.
Thymic Cyst and Hyperplasia Thymic cyst and “abnormal” thymic hyperplasia, though virtually unknown in adults, occur occasionally in children. Thymic tumors other than thymoma accounted for approximately 17% of anterior mediastinal masses in children and 1 to 2% of anterior mediastinal tumors in adults. Whether thymic hyperplasia should even be included in a discussion of primary mediastinal tumors is debatable. However, because there is often concern when the “normal thymic shadow” persists into late childhood, the inclusion seems warranted. An exhaustive review of the medical literature on thymic neoplasms in children less than 15 years of age over a 25-year period disclosed 170 patients in whom thymic hyperplasia was diagnosed roentgenographically and approximately 50 patients in whom resection was performed. The enlarged normal thymus did not appear as a forerunner of neoplastic change or immunological difficulty, and was not associated with hematological or metabolic disorders. Respiratory complications or symptoms were only occasionally reported. LaFranchi and Fonkalsrud [17], however, did report several cases of MG associated with thymic hyperplasia in children. Observation seems safe for the typical thymic shadow in asymptomatic infants up to 3 years of age, since involution can be expected in 98% of such enlargements [MI.In the older child, who is asymptomatic and who
has typical roentgenographic features of thymic hyperplasia, reliable observation with an annual chest roentgenogram also seems safe [MI. The development of symptoms or radiographic features not typical of thymic hyperplasia should prompt removal of the mass. The use of ”steroid testing” to “diagnose” thymic hyperplasia is not recommended, as this is highly nonspecific and causes lympholysis in any lymphatic tumor, for example, malignant thymoma.
Carcinoid Tumor Carcinoid tumor of the thymus is a rare, generally aggressive neoplasm that is wholly distinct from thymoma. Delineated in 1972 by Rosai and Higa [19], fewer than 100 confirmed or probable cases have been reported. Indeed, only recently has a clear representation of this anterior mediastinal neoplasm been presented and is largely due to the work of Wick and associates [20] at the Mayo Clinic. As longer follow up has become available, the malignant nature of thymic carcinoid has become more apparent. Primary mediastinal carcinoid, that is, thymic carcinoid, is believed to arise from a population of thymic cells of neural chest origin in contrast to the pharyngeal pouch derivation of the epithelial cells in thymoma. Ultrastructural studies of thymic carcinoid indicate a neuroectodermal embryohistogenesis, as is also the case with bronchial and duodenal carcinoids. Like the bronchus and duodenum, the thymus is of foregut origin. Thymic carcinoid occurs predominantly in men over a wide age range with an average age at diagnosis of 42 years. The carcinoid syndrome has not been reported in these patients, and serotonin is not generally isolated (using immunoperoxidase stains). These tumors do have the ability to secrete other APUD (amine precursor uptake, decarboxy1ase)-type hormones, that is amines, kinins, or prostaglandins, and approximately one-third of primary mediastinal carcinoids have been associated with paraneoplastic syndromes. Cushing’s syndrome, secondary to production of adrenocorticotropic hormone, is most common. In addition, a limited number of cases of thymic carcinoid have been reported in association with the multiple endocrine neoplasia syndrome, Type I, and two authors have reported its association with medullary carcinoma of the thyroid. In the absence of endocrine abnormalities, clinical manifestations of thymic carcinoids are those produced by any anterior mediastinal mass. Macroscopically, the tumors are often large, lobulated, and well vascularized, with gross invasion of surrounding structures occurring in half the patients. Typical cytoplasmic neurosecretory granules of carcinoids are present, but more importantly, in focal areas, primary mediastinal carcinoid can resemble thymoma, metastatic carcinoma, germ cell tumors, and malignant lymphoma [20]. Thus, it may be prudent to use the full armamentarium of microscopy and special staining techniques available when differential diagnosis encompasses these tumors because the prognosis and treatment differ greatly from other thymic tumors.
341 Collective Review: Mullen and Richardson: Primary Anterior Mediastinal Tumors
The 5-year survival approximates 15% for all treatment methods [20]. Thymic carcinoid, like carcinoids elsewhere, is slowly progressive, and many recurrences have been reported after 5 years. Death results from metabolic complications, local recurrence, and extrathoracic metastases, the last reported in 75% of patients. Skin and bone metastases are most common, and the mean survival after their appearance is 3 years [20]. Aggressive surgical extirpation is the treatment of choice for primary tumor and offers the only hope for cure in patients with disease amenable to resection. Irradiation and chemotherapy, alone or in combination with resection, have proved ineffective in either prevention or treatment of recurrent disease.
Thymic Carcinoma Although the benign or malignant nature of thymoma cannot usually be defined cytologically, there are occasional thymic tumors that are unequivocally malignant on cytological grounds. These tumors have been termed thymic carcinoma in contrast to malignant thymoma [21]. These tumors are rare, with squamous cell carcinoma and lymphoepithelioma-like carcinoma (10 and 13 cases reported, respectively) being the most common. The prognosis appears to be poor for squamous cell thymic tumors [22, 231.
Lymphatic Lesions Lymphomas commonly involve the mediastinum but rather infrequently present there solely [24]. The lymphatic tumors are found to be the most common cause of an anterior mediastinal mass in children, responsible for approximately 45%of such tumors, and the second leading cause of an anterior mediastinal mass in adulthood, accounting for nearly one-quarter of such lesions. The well-recognized entities of Hodgkin’s disease and nonHodgkin’s lymphoma [16] are seen commonly in the mediastinum, but the lesser common entity known as Castleman’s disease is also occasionally seen.
Hodgkin‘s Disease Hodgkin’s disease solely involving the mediastinum is a rather rare mode of presentation for this tumor. Johnson and co-workers [25] found mediastinal involvement in only 8.8% of patients from their review of five series in the literature. When limited to the mediastinum, the anterior compartment is by far the most common site of involvement, with 66 to 91% of cases localized there [24, 251. Although all of the particular subtypes of Hodgkin’s disease have been found in the mediastinum without involvement of other nodal groups, the unexplained high frequency of the nodular sclerosing variant has been noted repeatedly. Histological subtype enjoys a reputation of carrying a more favorable prognosis, both in Hodgkin’s disease localized to the mediastinum and elsewhere [24, 251. The average age at diagnosis of patients with mediastinal Hodgkin’s disease is approximately 30 years, somewhat younger than patients with other modes of presentation [24-261. The male to female ratio is approximately
equal [25]. Aside from the typical ”B’ symptoms (fever and night sweating) of Hodgkin’s disease, most patients are asymptomatic, with cough and hemoptysis almost never encountered [24]. Mediastinal Hodgkin’s disease tends to be quite bulky [27], a feature that makes the treatment controversial. If bulky disease is defined as a mediastinum to thorax ratio of greater than 0.30, treatment by conventional irradiation alone without whole-lung irradiation has resulted in a 50% relapse rate [27]. Furthermore, the size of the mediastinal mass appears to be the single most important variable in predicting relapse. Two large studies have shown greater than 80% complete remission with combination chemotherapy in patients who had relapse after radiation treatment only. Generally, the prognosis for patients with Hodgkin’s disease limited solely to the mediastinum is excellent [24].
Non-Hodgkin‘s Lymphoma Non-Hodgkin’s lymphoma presenting exclusively in the chest is very uncommon. Levitt and associates [28] found that of 215 patients with non-Hodgkin’s lymphoma, only 12 (5.6%)were seen with primary mediastinal involvement. All patients had an anterior mediastinal mass on chest roentgenogram. Lymphangiography, radionuclide scanning, and whole-body computed tomography were used to exclude disease outside the mediastinum. The average age at diagnosis is the early 30s, and more than three-fourths of the patients sought medical attention because of tracheal compression or chest pain [28, 291. Presenting symptoms are generally of brief duration from onset to diagnosis, and superior vena cava obstruction is not uncommon. Lymphoma presenting primarily in the mediastinum is virtually always of the diffuse histiocytic subtype [28, 291; however, the predominant cell type varies greatly in the two small series reported. The treatment of and prognosis for patients with primary mediastinal non-Hodgkin’s lymphoma are entirely unclear because of the small number of patients treated. Excision rarely leads to survival, but irradiation and chemotherapy appear to offer a better outcome [28]. Castleman‘s Disease In 1956, Castleman and associates [30]described a group of patients with benign mediastinal lymphoid mass that they titled mediastinal lymph node hyperplasia. Now often referred to as Castleman’s disease, the literature is replete with synonyms for this entity including angiofollicular lymph node hyperplasia [31], lymphoid hamartoma [32], angiomatous lymphoid hamartoma, giant hemolymph node, and follicular lymphoreticuloma. These lesions may occur anywhere in the body that lymph nodes can occur, although 70% are found within the mediastinum, predominantly in the anterior portion. Two specific histological types of Castleman’s disease have been identified. The most common is the hyaline vascular type, accounting for 90% of all lesions. Most patients with this type are young (70%less than 30 years
342 The Annals of Thoracic Surgery Vol 42 No 3 September 1986
old) and asymptomatic. Microscopically, these tumors present with small hyaline follicles and marked intrafollicular vascular proliferation [30]. The other is the plasma cell type that has larger follicles and intervening sheets of plasma cell, and is less vascular [33]. Approximately half of the plasma cell lesions are associated with fever, anemia, or hyperglobulinemia. An occasional patient with Castleman’s disease is seen with symptoms of tracheal compression. The etiology and pathogenesis of this entity remain undetermined. Castleman and associates [30] believed that the tumor represents exaggerated hyperplastic inflammatory response of the lymph nodes; others [32] consider it to be a benign hamartoma of the lymph nodes with a frequent vascular predominance. The radiographic features of Castleman’s disease are not specific. Contrast-enhanced computed tomography demonstrates vascular lesions in the hyaline vascular type and should prompt angiography prior to operative interventon. The hyaline vascular lesions demonstrate multiple feeding vessels, and a dense capillary phase shows less prominent computed tomographic and angiographic findings. Once discovered, these lesions have not been observed to grow, although most have been removed because of uncertainty of the diagnosis. Surgical excision appears certain in most patients and seems to totally ameliorate the systemic symptoms of the plasma cell variety.
Germ Cell Tumors Mediastinal germinal tumors are thought to arise in the thymus from primordial germinal rests that did not complete their migration from the urogenital ridge to the gonads during embryogenesis [34-361. The rarity of these tumors and their histological similarity to gonadal tumors have created some skepticism regarding primary extragonadal origin; however, it is now generally believed that they do arise as primary tumors, predominantly because of the extreme rarity with which germinal gonadal neoplasms metastasize solely to the anterior mediastinum [35, 371. Although precise classification and nomenclature are debatable, a system that separates these tumors into benign teratomas, malignant teratomas (including choriocarcinoma, yolk sac carcinoma, embryonal carcinoma, and teratocarcinoma), and seminomas seems most logical [36, 381. Fifteen percent of all mediastinal tumors are due to germ cell neoplasms in adults [36, 381, and they account for 24% of such neoplasms in children, representing the second most common cause of a primary anterior mediastinal mass in the pediatric age group. The anterior mediastinum is the most common location of an extragonadal germ cell neoplasm in the adult and is second only to the sacrococcygeal area for harboring such tumors in children [39].
Benign Teratoma Approximately 80% of all mediastinal germ cell tumors are benign teratomas [36]. The overwhelming majority are located anteriorly with only 3 to 8% arising from the
posterior mediastinum [40,41]. Benign teratomas exhibit a variety of mature tissues from the three germ cell layers, and because the ectodermal component is usually predominant, the term dermoid is often used to describe these tumors [37, 401. Grossly, benign teratomas are usually well encapsulated and appear cystic. The most common ectodermal tissue found on histological examination is skin (92% of patients), while smooth muscle is the major mesodermal component (70%)and respiratory epithelium constitutes the major endodermal tissue (60%)[37]. Most series find no difference in sex ratio between affected patients, and the diagnosis is made most often in the second or third decade of life [37, 411. These tumors are generally slow growing, and more than 50% of patients are asymptomatic [29, 41, 421. When symptoms are present, substernal chest pain and dyspnea are most common; however, expectoration of hair or sebaceous material, though very uncommon, represents a fistula between the tumor and the tracheobronchial tree and is virtually pathognomonic of a benign teratoma [37]. An occasional patient has clubbing of the fingers with cyanosis or a chest wall deformity [42], but the majority have a normal physical examination. The chest roentgenogram may be helpful because approximately one-fourth of benign teratomas display calcification of bone or teeth [37]. Computed tomography of the thorax may reveal cystic areas and differing densities consistent with fat, muscle, or other distinct tissue type. Ultimately, the diagnosis must be made histologically after surgical excision. Surgical extirpation should be prompt, as delayed removal has resulted in malignant degeneration [41, 421. Following removal, the prognosis is excellent, with virtually complete cure.
Malignant Teratoma The designation malignant teratoma encompasses a number of tumor types and is useful because the neoplasms included are separate from other germinal tumors, both clinically and with respect to their origin. Currently, it is thought that while seminomas arise directly from the germ cells, malignant teratomas have their origin in poorly differentiated embryonal carcinomas. The nonseminomatous germ cell tumors, that is, malignant teratomas, are very infrequent causes of a mediastinal mass. Considered as a group, they constitute approximately 12% of all germinal tumors found in the mediastinum, and they are found almost exclusively in the anterior compartment [39]. About 195 cases of pure and mixed types are reported in the literature with embryonal carcinomas, teratocarcinomas, and choriocarcinomas accounting for the majority [39]. Endodermal sinus tumor is extremely rare with approximtely 20 cases reported [431. Primary malignant mediastinal teratoma is a disease virtually restricted to young men [44,46]. Cough, hemoptysis, and progressive dyspnea are common. Gynecomastia and soft, small testes are found in half of these patients who usually have elevated p-human chorionic gonadotropin (P-HCG).
343 Collective Review: Mullen and Richardson: Primary Anterior Mediastinal Tumors
Ninety percent of patients with testicular tumors that are not seminomas have elevated levels of either P-HCG or a-fetoprotein (AFP) [47]. Approximately 70% of patients with these nonseminomatous tumors have elevated levels of AFP, and this often correlates with the presence of embryonal or yolk sac components [48]; elevated P-HCG is found in 60% of patients with these tumors [47]. In contrast, only 7% of seminomas are associated with elevated P-HCG, and AFP production has not been reported. Consequently, an elevated serum AFP concentration in a patient with a germ cell tumor is indicative of a nonseminomatous component, even if biopsy specimens reveal only pure seminoma [%I. These tumor markers will decline rapidly in the face of effective treatment because of their short half-lives (AFP, 5 days; P-HCG, 12 to 24 hours), and they also have been documented to reappear before obvious tumor recurrence [47]. All male patients with an anterior mediastinal mass, especially the young male patient, should have tumor marker assays determined. Abdominal computed tomographic scanning and careful physical examination of the testes to exclude the presence of testicular primary tumor should be done [45]. Suction biopsy of the testes has been recommended in patients seen with an apparent extragonadal germ cell tumor [47] because of the suggestion that testicular tumor microfoci may spontaneously regress and leave scars as markers of their presence. However, review of the cases of all patients with extragonadal germ cell tumors reported in the literature in whom the testes were studied microscopically disclosed scarring in only two instances [39,49]. Therefore, careful physical examination should suffice. Klinefelter’s syndrome appears to predispose to the development of germ cell tumors, especially nonseminomatous extragonadal tumors of the mediastinum. The treatment of these tumors is changing, but a combined multimethod approach appears to be the treatment of choice. The tumors are generally radioresistant, and intermittent combination chemotherapy with subsequent radical excision of remaining tumor seems the most beneficial regimen to date [34, 361.
Seminoma Seminoma is clearly the most common type of germ cell tumor to primarily affect the mediastinum (127 reported cases), with the anterior compartment being the exclusive site of origin [39]. The disease affects men in the third decade of life. Local symptoms are common at the time of diagnosis with only 20% of lesions located by incidental chest radiographs. The initial management of these patients should include surgical extirpation. Although these tumors are extremely radiosensitive [39], resection offers more tissue for serial sectioning to exclude concomitant nonseminomatous components. The presence of the latter changes the prognosis and may necessitate treatment revision. Presentation with fever, superior vena cava obstruction, supraclavicular or cervical node involvement, hilar extension of the cancer, and age greater than 35
years are risk factors that predispose to failure with radiotherapy alone [50]. Chemotherapy is reserved for patients with advanced disease [34] or with a high risk for recurrence after radiotherapy, as noted already. The prognosis for patients with primary mediastinal seminoma is generally good, with a 75% 5-year survival [50]. Death occurs mainly because of distant metastases; bone and lung are the most common metastatic sites.
Mesenchymal Tumors Sabiston and Oldham [51] found that mesenchymal tumors constituted 7% of adult and 70% of childhood primary mediastinal tumors and stated that mesenchyma1 tumors usually occur in the anterior mediastinum. In the series collected here, 75 primary mediastinal mesenchymal tumors were reported in adults; there is little indication as to the anatomical compartment of localization. The following list presents the classification of mediastinal mesenchymal tumors. Tumors of Fibrous Tissue, Adipose Tissue, Smooth Muscle, Striated Muscle Fibromatosis Fibrosarcoma Lipoma Xanthogranuloma Leiomyoma Benign mesenchymoma Malignant mesenchymoma Rhabdomyosarcoma Mesothelioma Tumors of Blood Vascular Origin Benign hemangiopericytoma Malignant hemangiopericytoma Hemangioendothelioma Hamartomatous angioma Tumors of Vascular Origin Lymphangioma Lymphangiosarcoma Lymphangiopericytoma These tumors are malignant or benign with equal frequency [41]; their behavior is similar to that of mesenchymal tumors found elsewhere [5]. Because of the wide variety of tumor types, a detailed discussion is impossible. Lipoma represents the most common type of tumor of mesenchymal origin found in the mediastinum, and a brief discussion of this entity is included. Mediastinal lipoma accounts for approximately 2% of all primary mediastinal neoplasms [52], and they are usually found in the anterior mediastinum. Microscopically, lipoma consists of adult adipose tissue with varying numbers of lymphocytes within the stroma. Despite their intrinsic benignity, these tumors are clinically very important because they tend to grow to enormous proportions (the largest reported weighed 7.9 kg) and cause compression to mediastinal structures. However, even large tumors are often asymptomatic, which is probably the result of total encapsulation and the lack of a firm
344 The Annals of Thoracic Surgery
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point of fixation within the mediastinum. Diagnosis is made only by histological confirmation of tissue type, and treatment is directed at complete surgical removal. Total extirpation is essential because these tumors have a tendency to recur.
Endocrine Tumors Thyroid tumors are relatively common causes of anterior mediastinal masses in the adult population, but they are almost nonexistent in children. Parathyroid lesions are occasionally encountered in adults in the anterior mediastinum but virtually never present a clinical problem in children.
Thyroid Tumors Most authors define intrathoracic goiter as occurring when the whole or the bulk of the goiter is situated within the mediastinum [53]. Thyroid neoplasms occurring separately or as ectopic thyroid tissue within the mediastinum are quite rare [3]. It is recognized from pathological studies that mediastinal goiters are almost always extensions of thyroid tissue in the neck; however, 75% of all mediastinal goiters are located in the anterior mediastinum [53]. Goiters found in the anterior mediastinum arise from the lower poles of the thyroid lobe or from the isthmus. Pathologically, the overwhelming majority are nontoxic adenomatous tumors, although carcinoma has been reported [54]. Degenerative changes such as hemorrhages, cyst formation, and calcifications are demonstrable in approximately 50%. The patient is usually in the sixth decade of life when the mass is discovered [53, 541, and women are affected three times as often as men. Clinically, because of their nontoxic nature, these masses are normally associated with euthyroidism; patients are seen with a palpable thyroid gland in the neck and an anterior mass on the chest roentgenogram. In the appropriate clinical setting [23], iodine 131 scanning is the method of choice in the diagnosis of intrathoracic goiter preoperatively [54, 551 because this technique is capable of detecting mediastinal thyroid tissue in nearly all instances [56]. Proper establishment of preoperative diagnosis is important in asymptomatic patients because surgical intervention may be obviated, and when operation is required, a less extensive technique may be used. The treatment in the symptomatic patient is total surgical excision. A neck incision will remove virtually all moderate-sized goiters in the anterior mediastinum. However, the surgeon should be prepared to extend the incision into the mediastinum through a sternotomy, if necessary. Technical difficulties such as large tumor size, vascular anomalies, or adhesions from previous operations could result in the need for an extended incision [53]. Parathyroid Tumors Among the ectopic locations of the parathyroid gland, the mediastinum is by far the most frequent. In several large series of parathyroid tumors, the incidence of
mediastinal parathyroid tissue has been reported at about 20% [57,58]. Nathaniels and colleagues [57]found that 80% of mediastinal parathyroid glands occur in the anterior mediastinum, and Wang [58] reported that 21 patients underwent reexploration for hyperparathyroidism and required mediastinal exploration to detect the aberrant gland. Two-thirds of the glands were located in the anterosuperior mediastinum. Most mediastinal parathyroid tumors probably originate in the lower parathyroid glands because of their close association with the thymus (both pharyngeal pouch 111 derivatives). Forty percent of lower glands are likely to be found within the thymic capsule in the lower neck or in close association with the thymus in the anterior mediastinum [57]. Carcinoma of the parathyroid is extremely rare in the mediastinum [3]. The symptoms are invariably those of primary hyperparathyroidism, and symptoms from the mass itself virtually never occur because of its small size. The neck incision is generally accepted as the primary approach for anterior parathyroid tumors, and mediastinotomy is used as necessary. Even with an initial failed neck exploration, a second cervical exploration will usually disclose the tumor. The use of the mediastinoscope is advocated at the first operation to facilitate mediastinal exploration; however, there is no large patient experience to prove the efficacy of this approach. The diagnosis of mediastinal parathyroid tumor in a patient with clinical findings confirming primary hyperparathyroidism is a formidable challenge. Procedures for detecting abnormal parathyroid glands include a variety of nuclear imaging techniques and invasive vascular procedures, but none have been proven beneficial in a large number of patients. If reexploration of the neck fails to demonstrate the adenoma, thymectomy should be performed. This procedure can often be done through a cervical approach, but a sternum-splitting incision may be needed.
References 1. Pokorny WJ, Sherman JO: Mediastinal masses in infants and children. J Thorac Cardiovasc Surg 68:869, 1974 2. King RM, Telander RL, Smithson WA, et al: Primary mediastinal tumors in children. J Pediatr Surg 17:512, 1982 3. Silverman NA, Sabiston DC Jr: Primary tumors and cysts of the mediastinurn. Curr Probl Cancer 2:1, 1977 4. Oldham HN Jr, Sabiston DC Jr: Primary tumors and cysts of the mediastinum. Monogr Surg Sci 4:243, 1967 5. Haller VA, Mazcer DO, Morgan WW: Diagnosis and management of mediastinal masses in children. ] Thorac Cardiovasc Surg 58:385, 1969 6. Oldham HN Jr: Mediastinal tumors and cysts. Ann Thorac Surg 11:246, 1971 7. Rubush JL, Gardner IC, Boyd WC, et al: Mediastinal tumors: review of 186 cases. J Thorac Cardiovasc Surg 65:216, 1973 8. Welch KJ, Tapper D, Vawter GP: Surgical treatment of thymic cysts and neoplasms in children. J Pediatr Surg 14:691, 1979 9. Cohen DJ, Ronnigen LD, Graeber GM, et al: Management
345 Collective Review: Mullen and Richardson: Primary Anterior Mediastinal Tumors
of patients with malignant thymoma. J Thorac Cardiovasc Surg 87:301, 1984 10. Gray GF, Gutowski WT: Thymoma, a clinico-pathologic study of 54 cases. Am J Surg Pathol 3:235, 1979 11. Appelqvist P, Kostianen L, Franssila K, et al: Treatment and prognosis of thymoma: a review of 25 cases. J Surg Oncol 20:265, 1982 12. Green AN, Srivastava SP, Burgess J: Thymoma: a ten-year review. Am J Surg 136:49, 1978 13. LeGolvan DP, Abell MK: Thymomas. Cancer 39:2142, 1977 14. Salyer WR, Eggleston JC: Thymoma: a clinical and pathological study of 65 cases. Cancer 37:229, 1976 15. Shamji F, Pearson FG, Todd TR, et al: Results of surgical treatment for thymoma. J Thorac Cardiovasc Surg 76:43, 1984 16. Blalock A, Mason MF, Morgan HJ, et al: Myasthenia gravis and tumors of the thymic region: report of a case in which the tumor was removed. Ann Surg 110:544, 1939 17. LaFranchi J, Fonkalsrud EW: Surgical treatment of lymphatic tumors of the mediastinum in children. J Thorac Cardiovasc Surg 65:8, 1973 18. Ellis FH, Kirklin JN, Hodgson JR, et al: Surgical implications of the mediastinal shadow in thoracic roentgenograms in infants and children. Surg Gynecol Obstet 100: 532, 1955 19. Rosai J, Higa E: Mediastinal endocrine neoplasm of probable thymic origin related to carcinoid tumor: clinicopathologic study of 8 cases. Cancer 29:1061, 1972 20. Wick MR, Carney JA, Bernatz PE, et al: Primary mediastinal carcinoid tumors. Am J Surg Pathol 6:195, 1982 21. Levine GD, Rosai J: Thymic hyperplasia and neoplasia: a review of current concepts. Hum Pathol 9:495, 1978 22. Snover DC, Levine GD, Rosai J: Thymic carcinoma: five distinct histological variants. Am J Surg Pathol 6451, 1982 23. Wick MR, Weiland LH, Scheithauer BW, et al: Primary thymic carcinomas. Am J Surg Pathol 6:613, 1982 24. Vaeth JM, Moskowitz SA, Green JP: Mediastinal Hodgkin‘s disease. AJR 126:123, 1976 25. Johnson DW, Hoppe RT, Cox RS, et al: Hodgkin’s disease limited to intrathoracic sites. Cancer 523, 1983 26. Schomberg PJ, Evans RG, O’Connell MJ, et al: Prognostic significance of mediastinal mass in adult Hodgkin’s disease. Cancer 53:324, 1984 27. Mauch P, Goodman K, Hellman 5: The significance of mediastinal involvement in early stage Hodgkin’s disease. Cancer 42:1039, 1978 28. Levitt LV, Aisenberg AC, Harris NL: Primary nonHodgkin’s lymphoma of the mediastinum. Cancer 50:2486, 1982 29. Lichtenstein AK, Levine A, Taylor CR, et al: Primary mediastinal lymphoma in adults. Am J Med 68:509, 1980 30. Castleman B, Iverson L, Menendez VP: Localized mediastinal lymph node hyperplasia resembling thymoma. Cancer 9:822, 1956 31. Walter JF, Rottenberg RW, Cannon WB, et al: Giant mediastinal lymph node hyperplasia (Castleman’s disease): angiographic and clinical features. AJR 130:447, 1978 32. Abell MR: Lymphoid hamartoma. Radio1 Clin North Am 615, 1968 33. Onik G, Goodman PC: CT of Castleman‘s disease. AJR 140:691, 1983 34. Economou JS, Trump DL, Holmes EC, et al: Management of primary germ cell tumors of the mediastinum. J Thorac Cardiovasc Surg 83:643, 1982 35. Luna MA, Valenzuela-Tamariz J: Germ cell tumors of the
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mediastinurn: postmortem findings. Am J Clin Pathol 65:450, 1976 Parker D, Holford CP, Begent RH: Effective treatment for malignant mediastinal teratoma. Thorax 38:897, 1983 Lewis BD, Hurt RD, Payne WS, et al: Benign teratomas of the mediastinum. J Thorac Cardiovasc Surg 86:727, 1983 Ovrum E, Birkeland 5: Mediastinal tumors and cysts: a review of 191 cases. Scand J Thorac Cardiovasc Surg 13:161, 1979 Aygum C, Slawson RG, Bajaj K, et al: Primary mediastinal seminoma. Urology 23:109, 1984 Weinberg B, Rose JS, Efremides SC, et al: Posterior mediastinal teratoma (cystic dermoid): diagnosis by computerized tomography. Chest 77:694, 1980 Wychulis AR, Payne WS, Clagett OT, et al: Surgical treatment of mediastinal tumors. J Thorac Cardiovasc Surg 62:379, 1971 Adebonojo SA, Nicola ML: Teratoid tumors of the mediastinum. Am Surg 42:361, 1976 Fox MA, Viv VA: Endodermal sinus (yolk sac) tumors of the anterior mediastinum. AJR 135:291, 1980 Martini N, Golbey RB, Hajdu 51, et al: Primary mediastinal germ cell tumors. Cancer 33:763, 1974 Levitt RG, Husband JE, Glazer GM: CT of primary germcell tumors of the mediastinum. AJR 142: 73, 1984 Sickles EA, BeCliveau RE, Wiernik PH: Primary mediastinal choriocarcinoma in the male. Cancer 33:1196, 1974 Javadpour N: The value of biologic markers in diagnosis and treatment of testicular cancer. Semin Oncol 6:37, 1979 Grigor KM, Detri JI, Kour J, et al: Serum alpha-fetoprotein levels in 153 male patients with germ cell tumors. Cancer 33:252, 1977 Johnson DE, Laneri JP, Mountain CF, et al: Extragonadal germ cell tumor. Surgery 73235, 1973 Hurt RD: Primary anterior mediastinal seminoma. Cancer 49:1658, 1982 Sabiston DC Jr, Oldham HN Jr: The mediastinum. In Sabiston DC Jr, Spencer FC (eds): Gibbons Surgery of the Chest. Fourth edition. Philadelphia, Saunders, 1983, p 406 Politis J, Funahashi A, Gehlsen JA, et al: Intrathoracic lipomas. J Thorac Cardiovasc Surg 77550, 1979 Rietz KA, Werner B: Intrathoracic goiter. Acta Chir Scand 119:379, 1960 Irwin R, Braman 5, Arvanitidis A, et al: 1311thyroid scanning in preoperative diagnosis of mediastinal goiter. Ann Intern Med 89:73, 1978 Nejatheino M, Stroshein AM: CT vs. iodine scanning in diagnosis of mediastinal thyroid. AJR 1392334, 1982 Glazer GM, Axel L, Moss AA: CT diagnosis of mediastinal thyroid. AJR 138:495, 1982 Nathaniels EK, Nathaniels AM, Wang C: Mediastinal parathyroid tumors: a clinical and pathological study of 84 cases. Am Surg 171:165, 1970 Wang C: Parathyroid re-exploration: a clinical and pathological study of 112 cases. Ann Surg 186:140, 1977 Luosta R, Koikkalainen K, Jyrala A, et al: Mediastinal tumors: a follow-up study of 208 patients. Scand J Thorac Cardiovasc Surg 12:258, 1978 Nandi P, Wong KC, Mok CK, et al: Primary mediastinal tumours: review of 74 cases. J R Coll Surg Edinb 25:460, 1980 Whittaker LD, Lynn HB: Mediastinal tumors and cysts in the pediatric patient. Surg Clin North Am 582393, 1973 Bower RJ, Kiesewetter WB: Mediastinal masses in infants and children. Arch Surg 112:1003, 1977
P h g y Anterior Mediastinal Tumors in dren and Adults Bradley Mullen, M.D., and J. David Richardson, M.D. ABSTRACT This review details pertinent anatomical, radiological, pathological, and clinical information regarding primary anterior mediastinal tumors. Although the majority of these lesions are included in one of several subgroups, for example, thymic tumors, teratomas, or thyroid abnormalities, other less common entities will occasionally be encountered by the practicing surgeon. Likewise, there are variations in the frequency distribution of anterior mediastinal lesions in children as opposed to adults. Management of these individual lesions is outlined. Primary anterior mediastinal tumors are uncommon clinical entities on which there are few systematic reports in the surgical literature. The majority of series report occurrence of mediastinal tumors in the anterior compartment. The anatomical boundaries of the mediastinum may be defined differently, thereby including or excluding tumors from the study. Although any anatomical division of the mediastinum is arbitrary, for the purposes of this review, the anterior compartment is defined as that area bounded by the sternum anteriorly, the heart posteriorly, the thoracic inlet superiorly, and the diaphragm below. Located in the anterior mediastinum are the thymus gland, the adipose, lymphatic, and areolar tissues, and the thyroid and parathyroid glands on occasion. The relative incidence of common primary anterior mediastinal tumors in a collected series of 702 adults is listed in Table 1, and the relative frequency of common lesions in 179 children is reported in Table 2. In only one series [l] was the anterior compartment not found to be the most common area from which the mediastinal tumors arose. The incidence of specific tumors differs slightly in the various series, although general tendencies are apparent, especially in adults. Thymic lesions are the most frequent in adults, and the vast majority are thymoma. Lymphoma is the second most common tumor, followed by endocrine and germ cell neoplasms (roughly equal in incidence). In children, lymphoma is the most common primary anterior mediastinal tumor. Germ cell neoplasms are the second most prevalent tumor, followed by thymic lesions and mesenchymal tumors. In children, thymic abnormalities consist primarily of hyperplasia and cysts; only 5 cases of thymoma have been reported [l, 21. No series involving either From the Department of Surgery, University of Louisville School of Medicine, Louisville, KY. Address reprint requests to Dr. Richardson, Department of Surgery, Ambulatory Care Building, University of Louisville, Louisville, KY 40292.
338 Ann Thorac Surg 42:338-345, Sep 1986
children or adults revealed a sex-linked predilection for these tumors, except for specific types of germ cell tumors known to occur virtually exclusively in the male sex.
Signs and Symptoms A variety of signs and symptoms ranging from those clearly nonspecific to those virtually pathognomonic may cause the patient with an anterior mediastinal tumor to be seen for evaluation. Although many lesions are found on routine chest roentgenograms, nearly twothirds of patients have specific symptoms [3]. The only exceptions seem to be in reports from military centers where large numbers of screening chest roentgenograms are made of healthy young people. The most common symptoms are chest pain, cough, and dyspnea caused by compression or invasion of contiguous structures. Chest pain usually signals the invasive spread of malignant neoplasia. Other less common symptoms include hemoptysis, dysphagia, hoarseness, Horner’s syndrome, vena caval obstruction, arrhythmias, fever, weakness, and weight loss. The presence of symptoms in a patient with an anterior mediastinal mass clearly has prognostic importance because malignant lesions are more often symptomatic than benign lesions [2, 31. For example, King and associates [2] observed that 23 (44%) of 52 patients with benign lesions were symptomatic, whereas 98 (72%) of 136 patients harboring malignancy complained of symptoms. Despite the tendency for malignant lesions to be more often symptomatic, the presence of symptomatology is not specific for malignancy. In the usual group of symptomatic patients, approximately half of the lesions will be benign and half, malignant [4]. Besides symptoms caused by compression and invasion, other signs and symptoms, such as endocrinological abnormalities, cardiovascular lesions, and associated systemic syndromes, frequently occur in association with anterior mediastinal tumors. Thymoma associated with myasthenia gravis (MG) is perhaps the classic example. Other examples are discussed in the sections dealing with the specific tumors. Collectively, an infant or child is more likely to have symptoms than an adult [l].Several reasons could account for this finding. 1. Children are more likely to have a malignancy than adults [5-71. 2. Because of the smaller size of the thoracic cavity in the child, any lesion is more likely to cause symptoms by compression or invasion. 3. The most common location of primary anterior medi-
339 Collective Review: Mullen and Richardson: Primary Anterior Mediastinal Tumors
Table 1. Relative Frequency of Common Primary Anterior Mediastinal Tumors in 702 Adults Study
Tumor
41
7
Thymic lesions Germ cell tumor
231 60 107 61
37 10 7 13
459 43
67 58
Lymphoma Endocrine tumor Total % of series
Incidence 38
60
Total
(%I
31 21 37 11
7 5 9 21
21 7 0 6
327 103 160 112
47 15 23 16
100 48
42 62
34 50
702
. . . . . .
59
...
Table 2. Relative Frequency of Common Primary Anterior Mediastinal Tumors in 179 Children Study
Incidence
Tumor
61
1
62
2
Total
(%)
Thymic lesion” Germ cell tumor
4 21 9 7
13 4 0 2
9 5 13 8
4 13 58 9
30 43 80 26
17 24 45 15
41 39
19 17
35 38
84 45
179
Lymphoma Mesenchymal tumorb Total % of series
...
”This includes thymic cyst, thymic hyperplasia, and thymoma bSee text for description of included tumors.
astinal tumors in children is near the trachea, which results in the high frequency of respiratory symptoms. In all patients with symptoms of respiratory distress, more than three-fourths were less than 2 years old, and nearly 80% of these infants had symptoms of tracheal compression.
Thymic Lesions Thymic lesions are the most common cause of a primary anterior mediastinal mass in adulthood, and the majority are either a benign or malignant thymoma. Though these thymic lesions are not common in childhood [8], cysts and hyperplasia represent the predominant pathological finding when tumor is confirmed. Thymoma is relatively unique among tumors because the prognosis appears to be more closely related to gross characteristics at operation than to histological appearance [9, 101. Indeed, degree of encapsulation and invasion of adjacent tissues define malignancy for these tumors rather than the histological appearance of the tumor cells [9, 111. Those tumors displaying cellular atypia and other characteristics usually considered as evidence of malignancy are included under the classification thymic carcinoma and are discussed later. Generally, thymoma is classified histologically into three types based on the predominant cell type: lymphocytic, epithelial, and lymphoepithelial (mixed). The tumor stage is determined by the extent of tumor invasion at
operation. Stage I disease is represented by intracapsular growth with the capsule remaining intact, and may be referred to as a benign thymoma. Stage I1 disease is indicated by growth into surrounding organs, particularly the mediastinal fat, pleura, or pericardium. Intrathoracic metastasis is classified as Stage I11 disease, whereas Stage IV lesions have extrathoracic metastasis. Remote metastases tend to occur in the liver, bone, and brain and are present in approximately one-quarter of patients with invasive thymoma who have operation (91. Typically, the patient with thymoma may be of either sex, will be in the fifth or sixth decade of life [8, 12-15] when the tumor is diagnosed, and will have a 50% chance of being asymptomatic [9,12,15] when the lesion is discovered on routine chest roentgenogram. Since the relationship between thymoma and MG was described in 1901 and Blalock and co-workers (161 reported the successful excision of a thymic cyst in a girl with MG, the association of thymoma and a variety of syndromes has been actively studied. Approximately 15% of patients with MG have thymoma [8], either benign or malignant, while 10 to 50% of patients with thymoma have MG. Other systemic syndromes occurring with thymoma include erythroid and neutrophil hypoplasia, pancytopenia, Cushing’s syndrome, DiGeorge syndrome, carcinoid syndrome, Lambert-Eaton syndrome, nephrotic syndrome, syndrome of inappropriate secretion of antidiuretic hormone, Whipple’s disease, lupus ery-
340 The Annals of Thoracic Surgery Vol 42 No 3 September 1986
thematosus, pemphigus, scleroderma, polymyositis, polyneuritis, polyarthropathy, myotonic dystrophy, Sjogren’s syndrome, Addison’s disease, hypogammaglobulinemia, and thyroid carcinoma [8, 91. Although an immune basis seems fairly clear, the exact etiology and pathogenesis linking these syndromes to the thymic abnormality remain to be clearly elucidated. Benign thymoma (Stage I) has an excellent prognosis with complete cure likely after total surgical excision. The recurrence rate following complete resection of benign thymoma is reported to be less than 2%. Five-year survival ranges from 80 to 100% for benign thymomas and from 23 to 54% for malignant thymomas. There are claims that thymoma patients with MG have a worse prognosis than those without it [ll], but this issue is far from settled. Shamji and associates [15] presented data demonstrating that MG apparently augments survival in affected patients. They believed the improved survival reflected improved long-term medical management of MG . In treating thymoma, aggressive surgical staging and total excision should be attempted [8, 91. Thymomas, even though extensive when first seen, must be considered to be adherent to and compressing adjacent structures rather than truly invasive. Although contiguous structures may need to be resected along with the tumor, in most instances, thymoma can be completely removed once the proper plane of dissection is established [8]. Complementary irradiation is required for Stage I1 or 111 lesions [8, 9, 111, and patients with Stage IV tumors may require irradiation and systemic chemotherapy.
Thymic Cyst and Hyperplasia Thymic cyst and “abnormal” thymic hyperplasia, though virtually unknown in adults, occur occasionally in children. Thymic tumors other than thymoma accounted for approximately 17% of anterior mediastinal masses in children and 1 to 2% of anterior mediastinal tumors in adults. Whether thymic hyperplasia should even be included in a discussion of primary mediastinal tumors is debatable. However, because there is often concern when the “normal thymic shadow” persists into late childhood, the inclusion seems warranted. An exhaustive review of the medical literature on thymic neoplasms in children less than 15 years of age over a 25-year period disclosed 170 patients in whom thymic hyperplasia was diagnosed roentgenographically and approximately 50 patients in whom resection was performed. The enlarged normal thymus did not appear as a forerunner of neoplastic change or immunological difficulty, and was not associated with hematological or metabolic disorders. Respiratory complications or symptoms were only occasionally reported. LaFranchi and Fonkalsrud [17], however, did report several cases of MG associated with thymic hyperplasia in children. Observation seems safe for the typical thymic shadow in asymptomatic infants up to 3 years of age, since involution can be expected in 98% of such enlargements [MI.In the older child, who is asymptomatic and who
has typical roentgenographic features of thymic hyperplasia, reliable observation with an annual chest roentgenogram also seems safe [MI. The development of symptoms or radiographic features not typical of thymic hyperplasia should prompt removal of the mass. The use of ”steroid testing” to “diagnose” thymic hyperplasia is not recommended, as this is highly nonspecific and causes lympholysis in any lymphatic tumor, for example, malignant thymoma.
Carcinoid Tumor Carcinoid tumor of the thymus is a rare, generally aggressive neoplasm that is wholly distinct from thymoma. Delineated in 1972 by Rosai and Higa [19], fewer than 100 confirmed or probable cases have been reported. Indeed, only recently has a clear representation of this anterior mediastinal neoplasm been presented and is largely due to the work of Wick and associates [20] at the Mayo Clinic. As longer follow up has become available, the malignant nature of thymic carcinoid has become more apparent. Primary mediastinal carcinoid, that is, thymic carcinoid, is believed to arise from a population of thymic cells of neural chest origin in contrast to the pharyngeal pouch derivation of the epithelial cells in thymoma. Ultrastructural studies of thymic carcinoid indicate a neuroectodermal embryohistogenesis, as is also the case with bronchial and duodenal carcinoids. Like the bronchus and duodenum, the thymus is of foregut origin. Thymic carcinoid occurs predominantly in men over a wide age range with an average age at diagnosis of 42 years. The carcinoid syndrome has not been reported in these patients, and serotonin is not generally isolated (using immunoperoxidase stains). These tumors do have the ability to secrete other APUD (amine precursor uptake, decarboxy1ase)-type hormones, that is amines, kinins, or prostaglandins, and approximately one-third of primary mediastinal carcinoids have been associated with paraneoplastic syndromes. Cushing’s syndrome, secondary to production of adrenocorticotropic hormone, is most common. In addition, a limited number of cases of thymic carcinoid have been reported in association with the multiple endocrine neoplasia syndrome, Type I, and two authors have reported its association with medullary carcinoma of the thyroid. In the absence of endocrine abnormalities, clinical manifestations of thymic carcinoids are those produced by any anterior mediastinal mass. Macroscopically, the tumors are often large, lobulated, and well vascularized, with gross invasion of surrounding structures occurring in half the patients. Typical cytoplasmic neurosecretory granules of carcinoids are present, but more importantly, in focal areas, primary mediastinal carcinoid can resemble thymoma, metastatic carcinoma, germ cell tumors, and malignant lymphoma [20]. Thus, it may be prudent to use the full armamentarium of microscopy and special staining techniques available when differential diagnosis encompasses these tumors because the prognosis and treatment differ greatly from other thymic tumors.
341 Collective Review: Mullen and Richardson: Primary Anterior Mediastinal Tumors
The 5-year survival approximates 15% for all treatment methods [20]. Thymic carcinoid, like carcinoids elsewhere, is slowly progressive, and many recurrences have been reported after 5 years. Death results from metabolic complications, local recurrence, and extrathoracic metastases, the last reported in 75% of patients. Skin and bone metastases are most common, and the mean survival after their appearance is 3 years [20]. Aggressive surgical extirpation is the treatment of choice for primary tumor and offers the only hope for cure in patients with disease amenable to resection. Irradiation and chemotherapy, alone or in combination with resection, have proved ineffective in either prevention or treatment of recurrent disease.
Thymic Carcinoma Although the benign or malignant nature of thymoma cannot usually be defined cytologically, there are occasional thymic tumors that are unequivocally malignant on cytological grounds. These tumors have been termed thymic carcinoma in contrast to malignant thymoma [21]. These tumors are rare, with squamous cell carcinoma and lymphoepithelioma-like carcinoma (10 and 13 cases reported, respectively) being the most common. The prognosis appears to be poor for squamous cell thymic tumors [22, 231.
Lymphatic Lesions Lymphomas commonly involve the mediastinum but rather infrequently present there solely [24]. The lymphatic tumors are found to be the most common cause of an anterior mediastinal mass in children, responsible for approximately 45%of such tumors, and the second leading cause of an anterior mediastinal mass in adulthood, accounting for nearly one-quarter of such lesions. The well-recognized entities of Hodgkin’s disease and nonHodgkin’s lymphoma [16] are seen commonly in the mediastinum, but the lesser common entity known as Castleman’s disease is also occasionally seen.
Hodgkin‘s Disease Hodgkin’s disease solely involving the mediastinum is a rather rare mode of presentation for this tumor. Johnson and co-workers [25] found mediastinal involvement in only 8.8% of patients from their review of five series in the literature. When limited to the mediastinum, the anterior compartment is by far the most common site of involvement, with 66 to 91% of cases localized there [24, 251. Although all of the particular subtypes of Hodgkin’s disease have been found in the mediastinum without involvement of other nodal groups, the unexplained high frequency of the nodular sclerosing variant has been noted repeatedly. Histological subtype enjoys a reputation of carrying a more favorable prognosis, both in Hodgkin’s disease localized to the mediastinum and elsewhere [24, 251. The average age at diagnosis of patients with mediastinal Hodgkin’s disease is approximately 30 years, somewhat younger than patients with other modes of presentation [24-261. The male to female ratio is approximately
equal [25]. Aside from the typical ”B’ symptoms (fever and night sweating) of Hodgkin’s disease, most patients are asymptomatic, with cough and hemoptysis almost never encountered [24]. Mediastinal Hodgkin’s disease tends to be quite bulky [27], a feature that makes the treatment controversial. If bulky disease is defined as a mediastinum to thorax ratio of greater than 0.30, treatment by conventional irradiation alone without whole-lung irradiation has resulted in a 50% relapse rate [27]. Furthermore, the size of the mediastinal mass appears to be the single most important variable in predicting relapse. Two large studies have shown greater than 80% complete remission with combination chemotherapy in patients who had relapse after radiation treatment only. Generally, the prognosis for patients with Hodgkin’s disease limited solely to the mediastinum is excellent [24].
Non-Hodgkin‘s Lymphoma Non-Hodgkin’s lymphoma presenting exclusively in the chest is very uncommon. Levitt and associates [28] found that of 215 patients with non-Hodgkin’s lymphoma, only 12 (5.6%)were seen with primary mediastinal involvement. All patients had an anterior mediastinal mass on chest roentgenogram. Lymphangiography, radionuclide scanning, and whole-body computed tomography were used to exclude disease outside the mediastinum. The average age at diagnosis is the early 30s, and more than three-fourths of the patients sought medical attention because of tracheal compression or chest pain [28, 291. Presenting symptoms are generally of brief duration from onset to diagnosis, and superior vena cava obstruction is not uncommon. Lymphoma presenting primarily in the mediastinum is virtually always of the diffuse histiocytic subtype [28, 291; however, the predominant cell type varies greatly in the two small series reported. The treatment of and prognosis for patients with primary mediastinal non-Hodgkin’s lymphoma are entirely unclear because of the small number of patients treated. Excision rarely leads to survival, but irradiation and chemotherapy appear to offer a better outcome [28]. Castleman‘s Disease In 1956, Castleman and associates [30]described a group of patients with benign mediastinal lymphoid mass that they titled mediastinal lymph node hyperplasia. Now often referred to as Castleman’s disease, the literature is replete with synonyms for this entity including angiofollicular lymph node hyperplasia [31], lymphoid hamartoma [32], angiomatous lymphoid hamartoma, giant hemolymph node, and follicular lymphoreticuloma. These lesions may occur anywhere in the body that lymph nodes can occur, although 70% are found within the mediastinum, predominantly in the anterior portion. Two specific histological types of Castleman’s disease have been identified. The most common is the hyaline vascular type, accounting for 90% of all lesions. Most patients with this type are young (70%less than 30 years
342 The Annals of Thoracic Surgery Vol 42 No 3 September 1986
old) and asymptomatic. Microscopically, these tumors present with small hyaline follicles and marked intrafollicular vascular proliferation [30]. The other is the plasma cell type that has larger follicles and intervening sheets of plasma cell, and is less vascular [33]. Approximately half of the plasma cell lesions are associated with fever, anemia, or hyperglobulinemia. An occasional patient with Castleman’s disease is seen with symptoms of tracheal compression. The etiology and pathogenesis of this entity remain undetermined. Castleman and associates [30] believed that the tumor represents exaggerated hyperplastic inflammatory response of the lymph nodes; others [32] consider it to be a benign hamartoma of the lymph nodes with a frequent vascular predominance. The radiographic features of Castleman’s disease are not specific. Contrast-enhanced computed tomography demonstrates vascular lesions in the hyaline vascular type and should prompt angiography prior to operative interventon. The hyaline vascular lesions demonstrate multiple feeding vessels, and a dense capillary phase shows less prominent computed tomographic and angiographic findings. Once discovered, these lesions have not been observed to grow, although most have been removed because of uncertainty of the diagnosis. Surgical excision appears certain in most patients and seems to totally ameliorate the systemic symptoms of the plasma cell variety.
Germ Cell Tumors Mediastinal germinal tumors are thought to arise in the thymus from primordial germinal rests that did not complete their migration from the urogenital ridge to the gonads during embryogenesis [34-361. The rarity of these tumors and their histological similarity to gonadal tumors have created some skepticism regarding primary extragonadal origin; however, it is now generally believed that they do arise as primary tumors, predominantly because of the extreme rarity with which germinal gonadal neoplasms metastasize solely to the anterior mediastinum [35, 371. Although precise classification and nomenclature are debatable, a system that separates these tumors into benign teratomas, malignant teratomas (including choriocarcinoma, yolk sac carcinoma, embryonal carcinoma, and teratocarcinoma), and seminomas seems most logical [36, 381. Fifteen percent of all mediastinal tumors are due to germ cell neoplasms in adults [36, 381, and they account for 24% of such neoplasms in children, representing the second most common cause of a primary anterior mediastinal mass in the pediatric age group. The anterior mediastinum is the most common location of an extragonadal germ cell neoplasm in the adult and is second only to the sacrococcygeal area for harboring such tumors in children [39].
Benign Teratoma Approximately 80% of all mediastinal germ cell tumors are benign teratomas [36]. The overwhelming majority are located anteriorly with only 3 to 8% arising from the
posterior mediastinum [40,41]. Benign teratomas exhibit a variety of mature tissues from the three germ cell layers, and because the ectodermal component is usually predominant, the term dermoid is often used to describe these tumors [37, 401. Grossly, benign teratomas are usually well encapsulated and appear cystic. The most common ectodermal tissue found on histological examination is skin (92% of patients), while smooth muscle is the major mesodermal component (70%)and respiratory epithelium constitutes the major endodermal tissue (60%)[37]. Most series find no difference in sex ratio between affected patients, and the diagnosis is made most often in the second or third decade of life [37, 411. These tumors are generally slow growing, and more than 50% of patients are asymptomatic [29, 41, 421. When symptoms are present, substernal chest pain and dyspnea are most common; however, expectoration of hair or sebaceous material, though very uncommon, represents a fistula between the tumor and the tracheobronchial tree and is virtually pathognomonic of a benign teratoma [37]. An occasional patient has clubbing of the fingers with cyanosis or a chest wall deformity [42], but the majority have a normal physical examination. The chest roentgenogram may be helpful because approximately one-fourth of benign teratomas display calcification of bone or teeth [37]. Computed tomography of the thorax may reveal cystic areas and differing densities consistent with fat, muscle, or other distinct tissue type. Ultimately, the diagnosis must be made histologically after surgical excision. Surgical extirpation should be prompt, as delayed removal has resulted in malignant degeneration [41, 421. Following removal, the prognosis is excellent, with virtually complete cure.
Malignant Teratoma The designation malignant teratoma encompasses a number of tumor types and is useful because the neoplasms included are separate from other germinal tumors, both clinically and with respect to their origin. Currently, it is thought that while seminomas arise directly from the germ cells, malignant teratomas have their origin in poorly differentiated embryonal carcinomas. The nonseminomatous germ cell tumors, that is, malignant teratomas, are very infrequent causes of a mediastinal mass. Considered as a group, they constitute approximately 12% of all germinal tumors found in the mediastinum, and they are found almost exclusively in the anterior compartment [39]. About 195 cases of pure and mixed types are reported in the literature with embryonal carcinomas, teratocarcinomas, and choriocarcinomas accounting for the majority [39]. Endodermal sinus tumor is extremely rare with approximtely 20 cases reported [431. Primary malignant mediastinal teratoma is a disease virtually restricted to young men [44,46]. Cough, hemoptysis, and progressive dyspnea are common. Gynecomastia and soft, small testes are found in half of these patients who usually have elevated p-human chorionic gonadotropin (P-HCG).
343 Collective Review: Mullen and Richardson: Primary Anterior Mediastinal Tumors
Ninety percent of patients with testicular tumors that are not seminomas have elevated levels of either P-HCG or a-fetoprotein (AFP) [47]. Approximately 70% of patients with these nonseminomatous tumors have elevated levels of AFP, and this often correlates with the presence of embryonal or yolk sac components [48]; elevated P-HCG is found in 60% of patients with these tumors [47]. In contrast, only 7% of seminomas are associated with elevated P-HCG, and AFP production has not been reported. Consequently, an elevated serum AFP concentration in a patient with a germ cell tumor is indicative of a nonseminomatous component, even if biopsy specimens reveal only pure seminoma [%I. These tumor markers will decline rapidly in the face of effective treatment because of their short half-lives (AFP, 5 days; P-HCG, 12 to 24 hours), and they also have been documented to reappear before obvious tumor recurrence [47]. All male patients with an anterior mediastinal mass, especially the young male patient, should have tumor marker assays determined. Abdominal computed tomographic scanning and careful physical examination of the testes to exclude the presence of testicular primary tumor should be done [45]. Suction biopsy of the testes has been recommended in patients seen with an apparent extragonadal germ cell tumor [47] because of the suggestion that testicular tumor microfoci may spontaneously regress and leave scars as markers of their presence. However, review of the cases of all patients with extragonadal germ cell tumors reported in the literature in whom the testes were studied microscopically disclosed scarring in only two instances [39,49]. Therefore, careful physical examination should suffice. Klinefelter’s syndrome appears to predispose to the development of germ cell tumors, especially nonseminomatous extragonadal tumors of the mediastinum. The treatment of these tumors is changing, but a combined multimethod approach appears to be the treatment of choice. The tumors are generally radioresistant, and intermittent combination chemotherapy with subsequent radical excision of remaining tumor seems the most beneficial regimen to date [34, 361.
Seminoma Seminoma is clearly the most common type of germ cell tumor to primarily affect the mediastinum (127 reported cases), with the anterior compartment being the exclusive site of origin [39]. The disease affects men in the third decade of life. Local symptoms are common at the time of diagnosis with only 20% of lesions located by incidental chest radiographs. The initial management of these patients should include surgical extirpation. Although these tumors are extremely radiosensitive [39], resection offers more tissue for serial sectioning to exclude concomitant nonseminomatous components. The presence of the latter changes the prognosis and may necessitate treatment revision. Presentation with fever, superior vena cava obstruction, supraclavicular or cervical node involvement, hilar extension of the cancer, and age greater than 35
years are risk factors that predispose to failure with radiotherapy alone [50]. Chemotherapy is reserved for patients with advanced disease [34] or with a high risk for recurrence after radiotherapy, as noted already. The prognosis for patients with primary mediastinal seminoma is generally good, with a 75% 5-year survival [50]. Death occurs mainly because of distant metastases; bone and lung are the most common metastatic sites.
Mesenchymal Tumors Sabiston and Oldham [51] found that mesenchymal tumors constituted 7% of adult and 70% of childhood primary mediastinal tumors and stated that mesenchyma1 tumors usually occur in the anterior mediastinum. In the series collected here, 75 primary mediastinal mesenchymal tumors were reported in adults; there is little indication as to the anatomical compartment of localization. The following list presents the classification of mediastinal mesenchymal tumors. Tumors of Fibrous Tissue, Adipose Tissue, Smooth Muscle, Striated Muscle Fibromatosis Fibrosarcoma Lipoma Xanthogranuloma Leiomyoma Benign mesenchymoma Malignant mesenchymoma Rhabdomyosarcoma Mesothelioma Tumors of Blood Vascular Origin Benign hemangiopericytoma Malignant hemangiopericytoma Hemangioendothelioma Hamartomatous angioma Tumors of Vascular Origin Lymphangioma Lymphangiosarcoma Lymphangiopericytoma These tumors are malignant or benign with equal frequency [41]; their behavior is similar to that of mesenchymal tumors found elsewhere [5]. Because of the wide variety of tumor types, a detailed discussion is impossible. Lipoma represents the most common type of tumor of mesenchymal origin found in the mediastinum, and a brief discussion of this entity is included. Mediastinal lipoma accounts for approximately 2% of all primary mediastinal neoplasms [52], and they are usually found in the anterior mediastinum. Microscopically, lipoma consists of adult adipose tissue with varying numbers of lymphocytes within the stroma. Despite their intrinsic benignity, these tumors are clinically very important because they tend to grow to enormous proportions (the largest reported weighed 7.9 kg) and cause compression to mediastinal structures. However, even large tumors are often asymptomatic, which is probably the result of total encapsulation and the lack of a firm
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point of fixation within the mediastinum. Diagnosis is made only by histological confirmation of tissue type, and treatment is directed at complete surgical removal. Total extirpation is essential because these tumors have a tendency to recur.
Endocrine Tumors Thyroid tumors are relatively common causes of anterior mediastinal masses in the adult population, but they are almost nonexistent in children. Parathyroid lesions are occasionally encountered in adults in the anterior mediastinum but virtually never present a clinical problem in children.
Thyroid Tumors Most authors define intrathoracic goiter as occurring when the whole or the bulk of the goiter is situated within the mediastinum [53]. Thyroid neoplasms occurring separately or as ectopic thyroid tissue within the mediastinum are quite rare [3]. It is recognized from pathological studies that mediastinal goiters are almost always extensions of thyroid tissue in the neck; however, 75% of all mediastinal goiters are located in the anterior mediastinum [53]. Goiters found in the anterior mediastinum arise from the lower poles of the thyroid lobe or from the isthmus. Pathologically, the overwhelming majority are nontoxic adenomatous tumors, although carcinoma has been reported [54]. Degenerative changes such as hemorrhages, cyst formation, and calcifications are demonstrable in approximately 50%. The patient is usually in the sixth decade of life when the mass is discovered [53, 541, and women are affected three times as often as men. Clinically, because of their nontoxic nature, these masses are normally associated with euthyroidism; patients are seen with a palpable thyroid gland in the neck and an anterior mass on the chest roentgenogram. In the appropriate clinical setting [23], iodine 131 scanning is the method of choice in the diagnosis of intrathoracic goiter preoperatively [54, 551 because this technique is capable of detecting mediastinal thyroid tissue in nearly all instances [56]. Proper establishment of preoperative diagnosis is important in asymptomatic patients because surgical intervention may be obviated, and when operation is required, a less extensive technique may be used. The treatment in the symptomatic patient is total surgical excision. A neck incision will remove virtually all moderate-sized goiters in the anterior mediastinum. However, the surgeon should be prepared to extend the incision into the mediastinum through a sternotomy, if necessary. Technical difficulties such as large tumor size, vascular anomalies, or adhesions from previous operations could result in the need for an extended incision [53]. Parathyroid Tumors Among the ectopic locations of the parathyroid gland, the mediastinum is by far the most frequent. In several large series of parathyroid tumors, the incidence of
mediastinal parathyroid tissue has been reported at about 20% [57,58]. Nathaniels and colleagues [57]found that 80% of mediastinal parathyroid glands occur in the anterior mediastinum, and Wang [58] reported that 21 patients underwent reexploration for hyperparathyroidism and required mediastinal exploration to detect the aberrant gland. Two-thirds of the glands were located in the anterosuperior mediastinum. Most mediastinal parathyroid tumors probably originate in the lower parathyroid glands because of their close association with the thymus (both pharyngeal pouch 111 derivatives). Forty percent of lower glands are likely to be found within the thymic capsule in the lower neck or in close association with the thymus in the anterior mediastinum [57]. Carcinoma of the parathyroid is extremely rare in the mediastinum [3]. The symptoms are invariably those of primary hyperparathyroidism, and symptoms from the mass itself virtually never occur because of its small size. The neck incision is generally accepted as the primary approach for anterior parathyroid tumors, and mediastinotomy is used as necessary. Even with an initial failed neck exploration, a second cervical exploration will usually disclose the tumor. The use of the mediastinoscope is advocated at the first operation to facilitate mediastinal exploration; however, there is no large patient experience to prove the efficacy of this approach. The diagnosis of mediastinal parathyroid tumor in a patient with clinical findings confirming primary hyperparathyroidism is a formidable challenge. Procedures for detecting abnormal parathyroid glands include a variety of nuclear imaging techniques and invasive vascular procedures, but none have been proven beneficial in a large number of patients. If reexploration of the neck fails to demonstrate the adenoma, thymectomy should be performed. This procedure can often be done through a cervical approach, but a sternum-splitting incision may be needed.
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