148 - Esophageal Diverticula
Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.
Title: General Thoracic Surgery, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > Volume II > The Mediastinum > Section XXIX - Primary Mediastinal Tumors and Syndromes Associated with Mediastinal Lesions > Chapter 173 - Thymic Tumors
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Chapter 173
Thymic Tumors
Thomas W. Shields
Thymic tumors present almost exclusively in the anterior mediastinal compartment. Mullen and Richardson (1986), in their collective review, reported that in the adult, thymic lesions accounted for 47% of masses in this compartment. In the total of 2,412 patients in a combined series (see Chapter 166), thymic lesions were second only to neurogenic lesions in total number of all mediastinal tumors and cysts in the adult. However, it is the opinion of most that, at the present time, the number of thymic lesions seen annually in adults exceeds the number of neurogenic lesions seen. These tumors are rare in children younger than the age of 16 years. However, Ramon y Cajal and Suster (1991), as well as Pescarmona (1992) and Kaplinsky (1992) and their colleagues, have reported a number of these tumors in children and have presented their histologic and immunochemical features.
There has been much controversy as to the classification of thymic lesions, particularly of the various tumors seen. In the latter 20th century, one of the most accepted classifications was that of Rosai and Levine (1976) (Table 173-1). However, presently, it would be appropriate from both clinical and pathologic viewpoints to exclude those tumors that do not arise from the thymic epithelium or the neuroendocrine cells located in the thymus. Thus, tumors of germ cell or lymphoid origin and metastatic lesions to the thymus are excluded in the present discussion. Likewise, thymic hyperplasia (see Chapter 155) and thymic cysts (see Chapter 197) are excluded in this consideration of thymic tumors. Moreover, a truly workable classification should be based either on the histologic features or the gross features of the lesion, but not on a combination of both. Consequently, in this discussion, thymic tumors are separated into four basic categories: epithelial cell tumors (thymomas), tumors of neuroendocrine origin, thymolipomas, and a miscellaneous group of rare tumors (neuroblastoma and ganglioneuroblastoma, malignant melanoma, thymic hemangiomas, and myoid tumors) (Table 173-2).
EPITHELIAL CELL TUMORS (THYMOMAS)
Location
Marchevsky and Kaneko (1992) state that about 95% of all epithelial cell tumors of the thymus (thymomas) occur in the anterior compartment of the mediastinum. They have been found outside the confines of the mediastinum (a) in the neck, as reported by Ridenhour (1970) and Fukuda (1980) and their colleagues; (b) in the left hilar region, as reported by Cosio-Pascal and Gonzalez-Mendez (1967); and (c) within the pulmonary parenchyma, as reported by McBurney (1951), Yeoh (1966), Kung (1985), Moran (1995a), and Veynovich (1997) and their associates. Within the mediastinum, thymomas also have been described to be located in the middle (visceral) compartment by Kojima and co-workers (2002) and in a supradiaphragmatic position by Perera and Wilson (1962), by my colleagues and me (1962), and recently by Carr and O'Keefe (2001). Cooper and Narodick (1972) reported one located in the visceral compartment extending into the paravertebral sulcus. Von Wadon (1934) reported a thymoma that presented as an intratracheal polyp. Thymomas also have been reported to be rare primary tumors of the pleura (see Chapter 67).
Pathologic Features
All thymomas are derived from the thymic epithelial cells. The epithelial components may be identified by several immunohistochemical techniques using reaction with various antibodies (see Table 155-2 in Chapter 155).
According to McKenna and colleagues (1989) only a small percentage of thymomas (4%) consist of a pure population of epithelial cells. All the others contain varying mixtures of epithelial cells and lymphocytes. As a consequence, thymomas historically have been divided primarily into
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four histologic subgroups, including the epithelial variant. Bernatz (1961) and Lewis (1987) and their associates suggest the lesions be classified as (a) predominantly lymphocytic thymoma when the tumor is made up of more than 66% lymphocytes; (b) predominantly epithelial thymoma when the epithelial cell represents 66% or more of the cell population; (c) mixed lymphoepithelial thymoma when neither of the aforementioned criteria is met; and (d) spindle cell tumor, which is a subtype of the epithelial variety and is separated from the latter by the histologic characteristics of the epithelial cells.
Table 173-1. Classification of Tumors of the Thymus | ||
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This relatively simplistic classification was found to be inadequate to classify satisfactorily many of the epithelial tumors as to their origin and immunohistochemical properties. As a result, the histologic classification of the thymic epithelial tumors underwent numerous changes during the last several decades of the 20th century. On one aspect, however, on which all investigators agree is that only the epithelial cells (cortical and medullary) take part in the malignant transformations that occur. The thymic lymphocytes may vary greatly in number in the various tumors observed, but these lymphocytes take no part in the neoplastic transformation that results in the formation of the various thymic epithelial tumors. The lymphocytes in most thymomas are small and mature appearing, without evidence of cytologic atypia. Variations in cell pattern are observed; however, no evidence of malignant change is evident. Mokhtar and associates (1984), by studying the reactions of the lymphocytes in thymomas to monoclonal and polyclonal antisera markers, concluded that these cells mirrored the lymphocytic phenotypes of the normal thymus.
Table 173-2. Classification of Thymic Tumors | |
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It had been an article of faith that all thymomas (except the thymic carcinomas) were composed of cytologically benign cells regardless of their benign or malignant behavior (i.e., invasion beyond the capsule of the tumor or the presence of local or distant metastasis). However, as early as 1987, Lewis and associates identified the presence of varying degrees of cellular atypia in 2% of the patients with otherwise typical benign thymomas. Similar and even more advanced atypical changes were subsequently noted in the malignant variants as well by Shimosato (1994), Hishima and colleagues (1994), Suster and Moran (1996), and Kuo and Chan (1998). In addition to these atypical increasing sites of atypia, areas of actual carcinoma were also identified in a small number of patients. These latter thymomas were most often of the cortical histogenetic type associated with areas of either well-differentiated or poorly differentiated squamous cell carcinoma. Suster and associates (1997) also described a thymoma with pseudosarcomatous stroma that simulated a carcinosarcoma. Most of these combined thymomas with areas of thymic carcinoma (atypical thymomas) behaved clinically
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more like typical thymomas than like the very aggressive thymic carcinomas that were easily identified. Nonetheless, these atypical lesions appeared to provide evidence of a continuum of recognizable neoplastic change from the benign-appearing thymic epithelial tumors to the obviously malignant thymic carcinomas. Thus, a perfectly normal (benign)-appearing thymic epithelial cell within a thymic tumor has, in fact, the potential for malignancy.
The nature of the epithelial cell components in the epithelial thymic tumors varies greatly. They may be either medullary or cortical cells in origin and may morphologically represent cells that are present in a mature or involuted gland. The organotypic features may likewise vary in their likeness to either a mature or involuted gland. As a rule, the epithelial cell component of the thymomas consists of large round, oval, or spindle-shaped cells. These cells tend to be grouped in clusters. The nuclei are vesicular with small nucleoli, and the cytoplasm is either eosinophilic or amphophilic with indistinct cell borders. The spindle cells may resemble fibroblasts and form whorls and fascicles; the epithelial nature of these cells has been established by ultrastructural studies and immunohistochemical techniques (see Chapter 155). Other microscopic features, as noted by Marchevsky and Kaneko (1992) and Kornstein (1995), may be observed in these lesions: rosettes, pseudoglands, glands, papillary structures, Hassall's corpuscles, myoid cells, keratinizing squamous epithelium, perivascular spaces, cysts, fibrous bands, squamous or medullary differentiation, and germinal centers. Each of these features occurs in varying percentages of these tumors, but other than the problem of occasional difficulties in differential diagnoses, these findings are of no major significance. Hofmann and Otto (1989) point out that the thymic epithelial cells can be arranged along blood vessels and give the appearance of a hemangiopericytoma; the spindle variety of the epithelial cell can grow in whorls or in a storiform pattern and may resemble a malignant fibrous histiocytoma; and rosette and glandular formation may mimic a metastatic adenocarcinoma. The true nature of thymic epithelial derivation of the cells and increased certainty of the tumor being a thymoma can be detected by immunohistochemical tissue-staining techniques with the use of antikeratin antibodies, as described by Battifora (1980) and L ning (1981) and their colleagues. Hofmann and associates (1984, 1985) described the various techniques of these immunohistologic studies in detail. Hirokawa and associates (1988) have reported the incidence of positive results of the various thymic epithelial markers in 45 thymomas. Cytokeratin was positive in 100%, thymosin 2 in 89%, thymosin 1 in 80%, Th-3 mouse thymic nurse cells in 78%, Leu-7 in 67%, and UH-1 (cortical epithelium of human thymus) in 60%. They concluded that about 85% of the thymomas were of cortical epithelial cell origin (see Chapter 155). This is in essential agreement with the studies of Marino and M ller-Hermelink (1985), who reported 55 of 58 thymomas (95%) to be of cortical epithelial cell origin. Kornstein and colleagues (1988) reported positive reactivity to cytokeratin in 94%, epithelial membrane antigen in 77%, and Leu-7 in 80% of thymic epithelial cell tumors studied. Some reactivity occurred to neuron-specific enolase, but little to no reactivity was seen to carcinoembryonic antigen or chromogranin.
As the result of these many immunohistochemical studies, M ller-Hermelink and colleagues (1985, 1986a, 1986b) suggested a histologic classification based on the presence of either medullary or cortical phenotypic differentiation in a given thymoma. They classified the thymomas as (a) medullary, (b) mixed, (c) predominately cortical (organoid), (d) cortical, and (e) well-differentiated thymic carcinomas. The medullary thymomas are related phenotypically to the medullary epithelial cells, and cortical thymomas are related to the cortical cells. The mixed tumors showed components of both types. Using this scheme, Ricci and colleagues (1989) observed that most patients with the medullary type had stage I disease, whereas most with the cortical type had stage III or IV disease as defined by the staging system of Masaoka and co-workers (1981). The medullary thymomas were composed of small- to medium-sized cells with irregular, often spindle-shaped nuclei devoid of nucleoli and low to moderate numbers of lymphocytes of the mature T cell type. The capsule was thick, but intratumoral fibrous septa were usually absent. Atypia was absent, and mitotic activity was low. In the mixed thymoma, two epithelial components were present, one of which was that found in a medullary thymoma and the other of which was lymphatic rich, mimicking cortical areas of the normal thymus. The organoid thymoma was predominantly cortical and showed a recapitulation of both cortical and medullary areas of the normal thymus gland, including the presence of Hassall's corpuscles. A complete fibrous capsule was frequently lacking. These organoid tumors had a high lymphocyte count, and only a few epithelial cells were evident; the epithelial cells were elongated and mimicked the cells of the normal corticomedullary junction. The cortical thymomas were lobulated tumors with interlobular fibrous septa and often an incomplete capsule. The epithelial cells were medium to large in size with round to oval nuclei that contained dispersed chromatin, prominent central nucleolus, and ill-defined cytoplasm. Squamous cell differentiation was often present at the periphery of the tumor. Lymphocytes were abundant and blastic in appearance. The well-differentiated thymic carcinomas were lymphocyte-poor tumors growing in solid epithelial strands and infiltrating extrathymic structures. Marked cytologic atypia and mitotic figures were in abundance. This classification was suggested to have independent prognostic implications. This concept was supported by Wilkins (1995), who noted only a few recurrences in patients with medullary or mixed tumors, whereas the recurrence rate was high in the cortical lesions. Rendina (1988), Ricci (1989), Pescarcoma (1990), and Quintanilla-Martinez (1994) and their associates also supported this classification.
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On the other hand, the studies of Shimosato (1994) and Regnard and colleagues (1996) did not agree with this classification, nor with its potential prognostic value, and noted invasion, even death, in patients with medullary-type tumors. The impression of Kornstein and associates (1988) and of Kornstein (1995) was that this classification was no more useful than the traditional classification.
In 1996, and subsequently in 1999, Suster and Moran presented a simplified conceptual approach to the classification of thymic epithelial tumors, as follows:
Thymoma, a well-differentiated thymic epithelial neoplasm characterized by a population of round or spindle-shaped epithelial cells without cytologic atypia intimately admixed with lymphocytes in various proportions. The thymoma resembles many or all of the architectural organotypic features of the normal mature (childhood) thymus or features that recapitulate the normal involuted thymus of the adult.
Atypical thymoma, moderately differentiated thymic neoplasms that are characterized by a predominantly epithelial cell population showing a moderate degree of atypia but retaining some of the organotypical features of thymic differentiation.
Thymic carcinoma, a poorly differentiated thymic epithelial neoplasm characterized by overt cytologic features of malignancy with total loss of organotypical features of differentiation of the normal thymus.
At about the same time, however, the World Health Organization (WHO) came out with a new histologic classification (which resembles that of the M ller-Hermelink classification) that appears as the classification of choice at this time. Rosai and Sabin (1999) published the WHO's classification in the second edition of WHO, Histological Typing of Tumors of the Thymus (Table 173-3), Dadmanesh and associates (2001) described succinctly this new classification: In this schema, thymomas are evaluated on the combined basis of the morphologic appearance of the neoplastic epithelial cells and the relative number of these cells vis vis the non-neoplastic lymphocytes. Type A stands for atrophic, representing the thymic cells of adult life; type B stands for bioactive, representing the biologically active thymus of the fetus and infant; and type C stands for carcinoma.
Table 173-3. The New World Health Organization Histologic Classification of Thymic Epithelial Tumors | ||
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Fig. 173-1. Type A thymoma (hematoxylin and eosin, original magnification 800). Cells with oval to spindle nuclei have bland nuclear features. Few lymphocytes. From Dadmanesh F, Sekihara T, Rosai J: Histologic typing of thymoma according to the new World Health Organization classification. Chest Surg Clin N Am 11:407, 2001. With permission. |
According to Dadmanesh and colleagues (2001), type A tumors are composed of oval or spindle-shaped epithelial cells lacking nuclear atypia and accompanied by few or no lymphocytes (Fig. 173-1). The tumors are encapsulated, although a few may invade the capsule and even extend into the adjacent fat or lung. Type AB tumors (Fig. 173-2) have foci of type A admixed with foci rich in lymphocytes as in type B thymomas. Type B tumors resemble the normal functional thymus and are subdivided into types B1, B2, and B3 on the basis of increasing epithelial-to-lymphocytic ratio and the emergence of atypia of the epithelial cells. Type B1 tumors resemble normal active thymus and are lymphocyte-rich, with some areas resembling the thymic medulla (Fig. 173-3). Type B2 tumors are likewise rich in lymphocytes,
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but foci of medullary differentiation are less evident or even absent. The epithelial cells are more numerous and are plump cells with vesicular nuclei and conspicuous nucleoli (Fig. 173-4). A palisading appearance may be present owing to perivascular arrangement of the cells. Type B3 tumors are composed mainly of round or polygonal epithelial cells in a sheetlike growth pattern and a lack or paucity of a lymphatic component (Fig. 173-5). Atypia may or may not be present. Foci of squamous metaplasia and perivascular spaces are common. Type C tumors are frankly malignant cells, and the cytoarchitecture is no longer specific to the thymus (Fig. 173-6). At least nine subtypes of type C tumors have been identified, and those may be further subdivided into low-grade and high-grade malignant tumors. These will be discussed subsequently in the section, Thymic Carcinomas (Type C Thymomas).
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Fig. 173-2. Type AB thymoma (hematoxylin and eosin, original magnification 100). Interface between a lymphocyte-rich area (right) and the lymphocyte-poor spindle cell component similar to that of type A thymoma (left). From Dadmanesh F, Sekihara T, Rosai J: Histologic typing of thymoma according to the new World Health Organization classification. Chest Surg Clin N Am 11:407, 2001. With permission. |
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Fig. 173-3. Type B1 thymoma (hematoxylin and eosin, original magnification 100). Marked predominance of lymphocytes. Area of medullary differentiation appears as sharply outlined lighter foci (center) with cluster of epithelial cells at its center. From Dadmanesh F, Sekihara T, Rosai JL Histologic typing of thymoma according to the new World Health Organization classification. Chest Surg Clin N Am 11:407, 2001. With permission. |
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Fig. 173-4. Type B2 thymoma (hematoxylin and eosin, original magnification 200). Predominance of lymphocytes, but epithelial cells are clearly visible and morphologically abnormal by virtue of the nuclear enlargement and nucleolar prominence. From Dadmanesh F, Sekihara T, Rosai J: Histologic typing of thymoma according to the new World Health Organization classification. Chest Surg Clin N Am 11:407, 2001. With permission. |
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Fig. 173-5. Type B3 thymoma (hematoxylin and eosin, original magnification 200). Predominance of neoplastic epithelial cells, but also a clearly identifiable lymphocytic component. From Dadmanesh F, Sekihara T, Rosai J: Histologic typing of thymoma according to the new World Health Organization classification. Chest Surg Clin N Am 11:407, 2001. With permission. |
As seen in Table 173-4, the new WHO classification (1999) resembles the Kirchner and M ller-Hermelink (1989) classification. The classification of Suster and Moran (1999) is quite different in that the term thymoma (well-differentiated tumors) is used to classify all categories except for type B3, which is classified as an atypical thymoma (moderately differentiated). The poorly differentiated tumors are type C or thymic carcinoma. Which classification will become more generally accepted remains to be seen. Regardless of this, it must be emphasized that microscopic or gross invasion beyond
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the capsule of any of the typical (well-differentiated) or type A tumors, including those through B2 and even probably also with atypical or B3 lesions, is probably of more prognostic significance than the histocytologic features. However, it should be noted that although the histology of thymic epithelial tumors has a disputed effect on the patient's prognosis, Okumura and associates (2001) were able to show that the incidence of invasive tumor increased with each advancing stage in the WHO classification: (a) type A, 12.5%; (b) type AB, 38.8%; (c) type B1, 40%; (d) type B2, 69.4%; (e) type B3, 80%; and (f) type C, 100%.
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Fig. 173-6. Type C thymoma (hematoxylin and eosin, original magnification 200). Thymic carcinoma, epidermoid nonkeratinizing. Edges of the tumor nodules are sharp, composed of malignant epithelial cells with eosinophilic cytoplasm. From Dadmanesh F, Sekihara T, Rosai J: Histologic typing of thymoma according to the new World Health Organization classification. Chest Surg Clin N Am 11:407, 2001. With permission. |
Table 173-4. Comparison of Three Main Histologic Classifications of Thymic Epithelial Neoplasms | ||||||||||||||||||||
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Fig. 173-7. Noninvasive cystic thymoma (original magnification 235). |
Other Macroscopic Features
Degenerative changes, especially hemorrhage, calcifications, and cystic changes, are frequently observed in thymic tumors. Rosai and Levine (1976) reported that microcysts are present in 16% to 40% of tumors, and Gray and Gutowski (1979) reported that macroscopic ones (i.e., grossly visible cysts) also are seen in as many as 40% of thymomas (Fig. 173-7). These cysts have no relationship to the invasiveness or noninvasiveness of the lesion or to the association of the tumor with the systemic disease syndromes often present with thymomas. According to Moran and Suster (2001), such changes (i.e., hemorrhage and necrosis) in well-encapsulated, noninvasive cysts do not portend an adverse prognosis. A grossly cystic thymoma must be differentiated from a true benign thymic cyst.
Gross Pathologic Features
Grossly, a thymoma may be round or oval and may vary greatly in size. Thymomas appear to have a bosselated outer surface but occasionally appear as a flattened mass simulating a fibrotic plaque. The parenchyma is a soft tan or gray-pink, fish-flesh colored tissue with visible lobules and readily apparent white-gray fibrous tissue septa (Fig. 173-8). In almost all instances, the tumor is contiguous with adjacent normal-appearing thymic tissue unless the entire gland has been replaced by the tumor (Fig. 173-9).
The most important gross features are the presence or absence of encapsulation of the tumor and the presence or absence of fixation to or, more important, gross invasion into adjacent structures.
The incidence of well-encapsulated noninvasive, benign thymomas (many of which would be classified as type A or AB in the new WHO classification) varies in the reported series from 40% to 70%. Bergh (1978) and Masaoka (1981) and their associates each reported a 40% incidence; Lewis and colleagues (1987) reported one of 68%. Occasionally, a well-encapsulated lesion shows microscopic invasion
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beyond the capsule and thus must be considered an invasive, malignant lesion. Kornstein and associates (1988) noted 9 of 51 grossly encapsulated lesions (17.6%) to have microscopic invasion through the capsule. They observed four local recurrences in the nine grossly encapsulated lesions that showed microscopic invasion through the capsule into the adjacent mediastinal fat, as contrasted to no local recurrences in the 42 patients with encapsulated thymomas without microscopic evidence of invasion through the capsule.
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Fig. 173-8. Solid noninvasive thymoma from a patient with myasthenia gravis. |
However, although the aforementioned authors, as well as Fujimura (1987) and Haniuda (1992) and their associates, reported no recurrence in patients with completely encapsulated thymomas, even the patients with well-encapsulated lesions without microscopic invasion through the capsule may have a small incidence of local recurrence, varying between 2% and 12%, as recorded by Fechner (1969) and Masaoka (1981), Monden (1985), and Lewis (1987) and their colleagues, so that even these noninvasive lesions must be considered to have a malignant potential.
Gross or microscopic invasion of thymomas is present in about 30% to 60% of cases, according to the studies of Verley and Hollmann (1985) and of Maggi (1986), Lewis (1987), and Kornstein (1988) and their associates. When invasion is present, the thymoma must be considered a malignant lesion regardless of the microscopic appearance or the cellular structure of the tumor (Fig. 173-10). In fact, even in a malignant thymoma, the cellular structure should be cytologically benign except for occasional atypia of the epithelial cells. The invasion of the tumor into an adjacent structure (e.g., mediastinal pleura, pericardium, lung, lymph nodes, great vessels, nerves, or chest wall) must, however, be documented microscopically to establish the malignant nature of the lesion. A small number of encapsulated lesions may be grossly fixed to one of the aforementioned structures, but invasion is not demonstrated microscopically. In this situation, the lesion must be considered noninvasive. As Lewis and colleagues (1987) noted, however, the patients with this subgroup of thymoma have a somewhat poorer long-term prognosis than the patients with nonadherent encapsulated tumors. Regnard and co-workers (1996) observed five local recurrences in the former subgroup but none in the nonadherent subgroup in a long-term follow-up of their patients. On the other hand, the prognosis in this adherent subgroup is generally not as poor as that seen when microscopic invasion is documented.
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Fig. 173-9. A. Gross specimen of thymoma, fibrous tissue septa prominent. B. Low-power magnification of thymoma showing typical lobules separated by the septa. Part B from Cove H: The mediastinum. In Coulson SF (ed): Surgical Pathology. 2nd Ed. Philadelphia: JB Lippincott, 1988. With permission. |
Local invasion may be limited to the most adjacent structures, but extensive spread to more distant sites within the
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thorax is not uncommon (Fig. 173-11). Those patients with spread to the diaphragm also may have transdiaphragmatic extension. Scatarige and associates (1985) recorded infradiaphragmatic invasion in 6 of 19 patients (31.5%) with advanced, extensive local disease. The sites included the right lateral liver surface, posterior pararenal space, left paraaortic region, perigastric soft tissues, and spinal canal. These authors suggested that such extension was best identified by upper abdominal computed tomography (CT) examination in those patients with demonstrated diaphragmatic involvement. A number of potential pathways of the subdiaphragmatic extension have been suggested. Zerhouni and colleagues (1982) note that such extension may occur through the retrocrural space (Fig. 173-12). The communications among the extrapleural space, retrocrural space, and posterior pararenal space have been confirmed by the studies of Borlaza and associates (1979). Kleinman and co-workers (1978) described a second potential pathway anteriorly through a potential midline defect as well as the two parasternal spaces of Larrey (i.e., the foramen of Morgagni). A third pathway is spread directly through the diaphragm itself.
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Fig. 173-10. Thymoma invading adjacent lung (hematoxylin and eosin, original magnification 25). From Cove H: The mediastinum. In Coulson SF (ed): Surgical Pathology. 2nd Ed. Philadelphia: JB Lippincott, 1988. With permission. |
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Fig. 173-11. Routes of intrathoracic spread of malignant thymoma. Anterolateral spread to produce distal implants in parietal pleura, local direct invasion of pleura to involve the lung, direct posterior extension to involve the wall of the aorta, and posterior spread through the mediastinum. A, aorta; Br, bronchus; E, esophagus; PA, pulmonary artery; PV, pulmonary vein; SVC, superior vena cava. From Zerhouni EA, et al: Invasive thymoma: diagnosis and evaluation by computed tomography. J Comput Assist Tomogr 6:92, 1982. With permission. |
In addition to local invasion, malignant thymomas, despite their benign histologic appearance, may infrequently metastasize to distant sites: pleural or pericardial implants, the lung or mediastinal lymph nodes, and extrathoracic sites such as bone, liver, central nervous system, and axillary or supraclavicular lymph nodes. Lewis and associates (1987), in a review of 283 noninvasive and invasive thymomas seen at the Mayo Clinic, reported an incidence of distant metastasis of 3%. Kornstein (1988) and Maggi (1986) and their associates and Verley and Hollmann (1985) reported that distant metastases occurred in patients with invasive tumors in 3%, 5%, and 7% of patients, respectively. In a small series of 36 patients with invasive thymomas, however, Batata and colleagues (1974)
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at Sloan-Kettering Memorial Hospital reported an incidence of 30%. Cohen and associates (1984), in a similar group of patients with invasive thymomas, reported an incidence of 26%. Blumberg and associates (1995), in a later review of the material at Memorial Sloan-Kettering Cancer Center, reported a similar overall distant metastatic rate of 29%. Thus, it is apparent that patient referral patterns are important in any evaluation of the data presented.
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Fig. 173-12. Route of infradiaphragmatic spread of malignant thymoma through the aortic hiatus. From Zerhouni EA, et al: Invasive thymoma: diagnosis and evaluation by computed tomography. J Comput Assist Tomogr 6:92, 1982. With permission. |
Table 173-5. Staging Schemes of Thymoma | ||||||||||||||||||||||||||||||||
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Because of the biologic variability of the epithelial cell tumors of the thymus, a number of classifications have been suggested to stage these lesions relative to their invasiveness, metastatic characteristics, and the potential prognosis of the various substages. The staging schemes of Bergh (1978) and Masaoka (1981) and their colleagues, as well as that of Suster and Moran (1996), are a few of the many suggested schemes, but presently, the scheme suggested by Masaoka and co-workers (1981) is the most commonly used (Table 173-5). However, the modifications of Masaoka and associates' (1981) scheme suggested by Trastek and Payne (1989) and that of Kornstein (1995) also would appear to be appropriate for general use (Table 173-6).
Haniuda and colleagues (1992) proposed the addition of the status of mediastinal pleural involvement (no adhesion to the tumor, P0; fixation but not invasion, P1; and microscopic invasion of the mediastinal pleura, P2) because of the greater likelihood of local recurrence with each advancing degree of involvement (P1 versus P0 and P2 versus P1).
Moreover, the French surgeons Verley and Holliman (1985), as well as Gamond s (1991) and Regnard (1996) and their associates, suggested the inclusion of the extent of resection, complete or incomplete, because the latter significantly
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lowered the survival rate in stage III disease. These schemata were variations of the staging of the Group d'Etudes des Tameurs Thymiques (French GETT classification, 1982) published by Gamond s and colleagues in 1991 (Table 173-7). Of these, that of Regnard and associates (1996) is the most complete and is more similar to the Masaoka scheme. Nonetheless, although the P factor and the completeness of resection should be considered when assigning a tentative prognosis in a given patient, neither needs to be incorporated into the basic staging system. Recently, Asamura and co-workers (2003) suggested a new staging system by combining stage I and stage II disease as stage 1, with capsular invasion being disregarded as a staging criterion. New stage II and III was then determined by size of the tumor, less than 10 cm or 10 cm or more in diameter, and whether one or more intrathoracic organs were involved. Stage IV remained the same. At the moment, the acceptance of this schema is questionable. Yamakawa and colleagues (1991) attempted to develop a tumor, node, metastasis (TNM) classification but essentially found it of no value for staging thymic epithelial tumors.
Table 173-6. Suggested Simplified Staging of Thymomas | ||||||||||||||||||
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Table 173-7. Staging (French Classification 1982): Groupe d'Etudes des Tumeurs Thymique (GETT 1982) | |||||||||||
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Table 173-8. Immunohistochemistry of Epithelial Thymomas | |||||||||||||||||||||||||||
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Immunohistochemical Studies
Immunohistochemical studies of thymomas, at present, are primarily used in the identification of thymic epithelial cells to distinguish thymoma from lymphoma or other malignant anterior mediastinal tumors. According to Kornstein and colleagues (1988), antibodies to cytokeratin are most useful. Also, the finding that the lesion is negative for chromogranin provides a basis for the distinction between thymic carcinoids (positive for chromogranin) and a true epithelial thymoma (negative for chromogranin). The immunohistochemistry of thymomas is presented in Table 173-8. Pan and colleagues (2001) have presented data that B lymphocyte associated CD20 antigen is present in the epithelial cells (spindle cells) in most type A and type AB thymomas, whereas the epithelial cells in type B1 to B3 thymomas and those in thymic carcinomas did not express this antigen. The explanation for these differences remains to be elucidated.
Tomita and colleagues (2002) have reported that there may be an association between tumor angiogenesis [and vascular endothelial growth factor expression (VEGF)] and the invasiveness of thymic epithelial tumors. In immunohistochemical studies of 46 resected tumors (18 noninvasive thymomas, 20 invasive thymomas, and 8 thymic carcinomas), the mean microvessel densities were 4.6 3.2, 12.4 7.5, and 34.4 16.7, respectively. VEGF expression was present in 5.6%, 55.0%, and 62.5%, respectively, in the three aforementioned tumor subsets. From these data, the authors suggested that there was a significant correlation between tumor angiogenesis and invasiveness. Additional studies on tumors separated into the subgroups of the WHO classification are necessary to define the importance of the presence of VEGF expression and tumor angiogenesis.
Clinical Presentation
Most patients with thymomas are adults in the fifth and sixth decades of life, although thymomas may occur at any age. A thymoma is only infrequently discovered in children. Whittaker and Lynn (1973) reported no cases in 105 children with mediastinal lesions seen at the Mayo Clinic. Isolated case reports have appeared in the literature since their report, however, and these cases were reviewed by Furman and associates (1985). La Franchi and Fonkalsrud (1973) reported four benign and three malignant thymomas in children younger than 20 years of age; the youngest was 4 and the oldest 19 years of age. Welch and associates (1979) reported five malignant lesions, only three of which meet the present-day criteria of an epithelial thymoma; only two patients were younger than the age of 16 years. In Lewis and colleagues' (1987) series from the Mayo Clinic, no patients
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with a thymoma were younger than the age of 16 years. However, Ramon y Cajal and Suster (1991) and Pescarmona and associates (1992) recorded 10 and 5 typical lymphocytic thymomas in children, respectively. In Ramon y Cajal and Suster's (1991) series, 10 cases of heterogeneous groups of thymic tumors were described. Nine were symptomatic. Four presented with Masaoka stage I tumors, one with a stage IIb tumor, and five with IVb tumors. One tumor appeared to have the classic features of type A thymoma, four were of the mixed type (AB thymoma), two were of type B3 with significant atypia, and three were typical thymic carcinomas (type C). Two in the latter group were small cell carcinomas (these lesions now would be classified as neuroendocrine carcinomas); the third was an anaplastic carcinoma. Survival was related to histologic subtype: 8 months for type C, and 15 to 72 months for type B3, although multiple recurrences and metastases were seen. The best survival was noted in type A and the mixed type (AB); no metastases or recurrences were reported in 8 months to 3 years of follow-up.
In adults, the sex distribution is about equal between men and women. In the various series reported, there may be a slight preponderance of one gender or the other, but in the overall numbers, no significant difference occurs.
Patients with thymomas are often clinically asymptomatic. The exact percentage is difficult to ascertain, although 50% is often quoted. The symptomatic patients may have only local symptoms related to the presence of the tumor within the mediastinum or only symptoms related to the systemic disease states that are frequently associated with the presence of a thymoma, or a combination of both. As a consequence of this, as well as to the marked differences in the classification of thymic tumors in the past, it is impossible to state with assurance the number of truly symptomatic patients. In most reviews in the literature, about 30% to 40% of patients have local symptoms, and 30% to 50% have an associated systemic parathymic disease syndrome. The overlap of the two categories of symptoms occurs frequently but is not often separated in the available reviews.
Local Symptoms and Signs
As noted, probably 50% to 60% of patients are asymptomatic relative to the presence of the thymoma within the chest. When locally symptomatic, however, vague chest pain, shortness of breath, and cough are the common complaints. Severe chest pain, superior vena cava obstruction, paralysis of a hemidiaphragm as a result of involvement of a phrenic nerve, and hoarseness caused by involvement of a recurrent laryngeal nerve are infrequent but ominous signs of extensive malignant disease. The presence of a pleural or pericardial effusion is likewise a serious clinical finding. On a rare occasion, a thymoma will spontaneously rupture, with resulting acute mediastinal hemorrhage associated with severe chest pain and dyspnea. Radiographs will reveal mediastinal widening. Hemothorax is often present. Appropriate radiographic studies will rule out a major vascular tear. Stabilization of the patient and subsequent thymectomy are indicated. Only a few cases have been recorded in the literature, such as those reported by Caplin (1985), Templeton (1988), Fukuse (1991), and Shimokawa (2001) and their colleagues. Carr and O'Keefe (2001) reported the spontaneous infarction of an ectopically located thymoma, but rupture of the resulting cyst did not occur.
Lewis and associates (1987) reported the presence of weight loss, fatigue, fever, night sweats, and other constitutional symptoms in 18% of their patients with thymoma. The clinical significance of these constitutional findings is difficult to determine.
Associated Systemic (Parathymic) Disease States
A thymoma is rare; thus, its coincidence with other conditions is noteworthy and eventually may lead to further understanding of thymic function in health and disease. In Rosenow and Hurley's (1984) review, 40% of patients with thymoma had a parathymic syndrome, and one third of this group had two or more parathymic syndromes. Table 173-9 lists the clinical disorders associated with thymomas, and Table 173-10 lists the varying incidences of the more common parathymic syndromes that were published by Verley and Hollmann (1985) as well as by Souadjian (1974) and Lewis (1987) and their colleagues.
Myasthenia Gravis
Myasthenia gravis is the most commonly associated disease. This syndrome is present in about 30% of patients with thymomas. Higher incidences have been reported by Lewis (1987), Maggi (1986), and Monden (1984) and their associates 46%, 73%, and 59%, respectively. These high incidences are undoubtedly the result of specific patient referral patterns. These patients tend to be, on average, 10 to 15 years older than patients with myasthenia without tumor and somewhat younger than patients who have thymoma without this complication. Patients with thymoma and myasthenia gravis may have any type of thymoma, except that its occurrence with the type A thymoma (spindle cell, medullary) variety is rare, as noted by Lewis (1987), Verley and Hollmann (1985), and Maggi (1986, 1991) and their colleagues. Kirchner and associates (1992) reported a marked association of squamous elements in thymomas with myasthenia gravis. Kornstein (1995) could not confirm this finding. Although the association of myasthenia with thymoma is usually simultaneous, thymomas have been recognized years after the onset of myasthenia; conversely, myasthenia has developed promptly or even years after the removal of a thymic neoplasm, as noted by Namba and colleagues in their report in 1978. Onoda and associates (1996) described the onset of fulminant myasthenia gravis after the removal of a misdiagnosed thymoma. Medical therapy as well as subsequent completion thymectomy was necessary for control of the patient's disease. Mulder (1996),
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in an invited commentary, suggested that, at the time of removal of any unknown anterior mediastinal mass, an immediate histologic diagnosis be obtained so that a total thymectomy can be done if the tumor indeed is a thymoma because the onset of postoperative myasthenia gravis, although uncommon, is not rare. Namba and colleagues (1978) have discussed the vagaries of this occurrence.
Table 173-9. Clinical Disorders Associated with Thymomas | ||
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In the reviews of Lewis (1987), Maggi (1986, 1991), Pescarmona (1990), Crucitti (1992), Lardinois (2000), Okumura (2001), and de Perrot (2002a) and their colleagues, the presence or absence of myasthenia gravis has little overall affect on either the local presentation, clinical behavior, or prognosis of a thymoma. Monden and associates (1984, 1985), however, reported data that suggest that a nonmyasthenic thymoma behaves in a more malignant fashion than does a myasthenic thymoma. Elert and colleagues (1988) noted that patients with myasthenia gravis and a thymoma presented at an earlier stage (only 19% of these patients had an advanced stage of the tumor and had a poorer prognostic outlook) and had a better prognosis than those patients with a thymoma without myasthenia gravis. Moore and associates (2001) have made a similar observation. These observations need further clinical documentation.
Table 173-10. Incidence of Conditions associated with Thymomas | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Recently, Okumura and colleagues (2001) noted that myasthenia was not seen with type A or type C thymomas but occurred in patients with the B varieties (Table 173-11). However, Pan and associates (2001) have seen several patients with type A thymomas and myasthenia gravis. Earlier,
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Hirokawa and colleagues (1988) reported that all 10 of the thymomas associated with myasthenia gravis in their series of 45 thymomas were positive by immunohistochemical techniques for UH-1 and Leu-7. As a consequence, they considered all of these thymomas of cortical epithelial cell origin.
Table 173-11. Myasthenia Gravis Tumor Type and Number of CD4+/CD8+ Lymphocytes | ||||||||||||||||||||||||
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In contrast to the high incidence of myasthenia gravis in patients with thymoma, only 5% to 15% of patients with myasthenia gravis have thymomas.
Pure Red Cell Aplasia
The association of thymoma with severe anemia caused by suppression of erythrogenesis in the bone marrow is well established. Whereas red cell precursors are greatly reduced or absent, myelopoiesis and megakaryocytopoiesis usually are normal or increased. Burrows and Carroll (1971), however, reported the occurrence of pancytopenia. The mechanism of this erythrocyte aplasia is not clear, but evidence put forth by Jepson and Vas (1974) suggests that it is mediated immunologically. The presence of immunoglobulin G antibodies that inhibit erythropoietin or hemoglobin synthesis, or both, and that are cytotoxic for erythroblasts has been observed in these patients. The immunodeficiency is generally attributed to a decreased number of B lymphocytes in the bone marrow and peripheral blood, as noted by Cooper and Butler (1989). The T cells are usually normal in number, although some patients have some changes in cellular immunity. Of 56 patients with red cell aplasia reviewed by Hirst and Robertson (1967), 7 also had myasthenia gravis, and 2 had hypogammaglobulinemia. Of interest was the report of Suzuki and colleagues (1995) on the occurrence of both pure red cell aplasia and myasthenia gravis after resection of an invasive thymoma.
Fifty percent of patients with red cell aplasia have associated thymomas, but only 5% of patients with thymoma have the disorder. According to Beard and colleagues (1978), most of these patients (about 70%) have a noninvasive spindle cell variant of thymoma (type A).
Although Zeok and associates (1979) reported that about 25% to 33% of patients with red cell aplasia benefit from the excision of the thymoma and that most, as noted, are associated with type A (the spindle cell subtype) thymoma, which normally has a good prognosis, this group of patients as a whole has a poorer prognostic outlook than those patients without this autoimmune disease. Kaiser and Martini (1989), as well as Masaoka (1989), Maggi (1991), and Murakawa (2002) and their colleagues, have documented this observation.
Immunoglobulin Deficiency
The association of thymoma, particularly type A (the spindle cell type of thymoma), and acquired hypogammaglobulinemia, first reported by Good (1954), has been described in about 10% of patients with an immunoglobulin deficiency. The syndrome may occur in a previously normal patient after the removal of a thymoma. Waldmann and co-workers (1975) reported that this acquired hypogammaglobulinemia occurs mainly in elderly patients. These authors demonstrated a population of suppressor T cells inhibiting immunoglobulin synthesis in several patients with thymoma, although most patients with the syndrome have normal numbers of circulating T cells, normal results of in vitro immunologic tests, and normal skin reactivity to common antigens. Removal of the thymoma is not beneficial in ameliorating the syndrome. The prognosis for these patients is poor.
Systemic Lupus Erythematosus
The association of systemic lupus and a thymoma is seen infrequently. Maggi and colleagues (1991) reported this combination in 2.5% of their 241 patients, and Verley and Hollmann (1985) observed the combination of the two in 1.5% of their 200 patients. Removal of the thymoma has no effect on the course of the systemic disease. The prognosis in these patients also is poor.
Ulcerative Colitis
Souadjian and colleagues (1974) at the Mayo Clinic reported that ulcerative colitis was present in 2 (0.3%) of 598 patients with a thymoma. At best, this is a tenuous association and may be only coincidence. However, Tsuchiya and associates (1991) reported that the use of thymectomy (no thymomas included) showed some effectiveness in the management of the patient's ulcerative colitis. However, the evaluation of the data by the authors is somewhat controversial. Therefore, the case report by Okubo and coauthors (2001) is of interest. They reported that after the complete resection of a type AB, Masaoka stage III thymoma and postoperative irradiation in a 51-year-old woman with ulcerative colitis, a colonoscopy 10 months after the thymectomy revealed no evidence of ulcerative colitis. At the time of the report, the patient was free of colonic disease for more than 22 months. Whether this was the result of a cause and effect of the resection of the thymoma or simply a spontaneous remission remains to be seen.
Nonthymic Cancer
The causal relationship of a thymoma and a subsequent nonthymic cancer remains obscure. However, the incidence of a second primary cancer of another organ system in patients who have had a thymoma is impressive. It was observed in 17% of the patients reviewed by Lewis and associates (1987) from the Mayo Clinic, and Couture and Mountain (1990) from the M. D. Anderson Cancer Center reported an incidence of 21%. Although other series have reported lower incidences of a second tumor, the significance of these observations is that the long-term follow-up of the patients
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who have had a thymoma removed must be especially vigilant to detect the presence of a second primary as early as possible.
Inappropriate Antidiuretic Hormone Secretion
Clinically symptomatic inappropriate antidiuretic hormone secretion by a thymoma has been recorded rarely. Almog and colleagues (1983) and Rosai, as noted by Argani and associates (1997), both reported the occurrence of symptomatic inappropriate antidiuretic hormone secretion in a malignant thymoma and a spindle cell thymoma, respectively.
Diagnostic Studies
Radiologic Studies
The standard posteroanterior and lateral chest radiographs are reliable means of detection of most thymomas. On the posteroanterior view, the lesion most often appears as a smooth or somewhat lobulated mass in the upper part of the chest overlying the superior portion of the cardiac shadow near the junction of the heart and great vessels. It may be in the midline, but more often than not, the mass projects more predominantly into one or the other hemithorax rather than equally into both hemithoraces. On the right side, the silhouette sign is present, and the ascending arch of the aorta is obliterated. On the left side, the sign is absent, and the aortic knob can be recognized behind the mass (Fig. 173-13). Other intrathoracic locations can occur, but nothing distinctive suggests that the mass is a thymoma in such situations (Fig. 173-14). The trachea rarely is displaced, unless an extensive invasive thymoma is present. Calcifications can be seen in about 10% of patients. Curvilinear and peripheral calcification indicates benignity. Scattered amorphous calcification within a tumor has been seen in both noninvasive and invasive thymomas.
On the lateral view, the mass opacifies the anterior cardiac window to a greater or lesser extent (Fig. 173-15). In patients with a small thymoma, the lateral radiograph often is the only view that suggests the presence of a lesion. As a consequence, all patients with myasthenia gravis or other systemic states that may accompany a thymoma must have lateral radiographs of the chest obtained. However, a CT scan of the chest has become the radiographic study of choice. All myasthenia patients should have periodic radiographic evaluation (CT scan) of the chest because a thymoma may develop at any time during the course of the disease.
CT may help to delineate the extent of the mass, and infrequently, a thymoma may be detected that was not seen on standard radiography (Fig. 173-16). CT is unreliable in differentiating a noninvasive from an invasive lesion, except in unusual circumstances. In these instances, narrowing of the trachea or vena cava, associated pleural or pericardial effusion, or possible metastatic pulmonary nodules at times is identified (Fig. 173-17). Zerhouni and associates (1982) documented the value of CT in assessing the intrathoracic spread of an invasive thymoma, which often is poorly defined by standard radiographic studies. As previously noted, Scatarige and colleagues (1985) suggest that all patients with invasive thymomas involving the diaphragm also should undergo CT of the upper abdomen to detect any subdiaphragmatic spread.
Magnetic resonance imaging adds little as a rule to the evaluation of the patient but may be of greater value in judging invasion by the tumor than CT. Sakai and colleagues (1992) also reported, however, that the findings of an inhomogeneous, high-intensity appearance and a lobulated internal structure are suggestive of the presence of an aggressive, invasive thymoma.
Surgical Biopsy
Biopsy of a suspected, locally asymptomatic thymoma preoperatively is unnecessary, even though it is advocated by some groups, as reported by Patterson (1992). It may even be contraindicated because the capsule of the tumor, of necessity, must be violated by an invasive technique. Although not proven, this intrusion may jeopardize the excellent surgical results obtained after the excision of a completely encapsulated lesion.
When the anterior mediastinal mass cannot be distinguished readily from one of the other malignant tumors of the anterior mediastinum (e.g., a lymphoma, malignant germ cell tumor, or metastatic lung cancer, to name a few), is locally symptomatic, or is clearly nonresectable, a biopsy is indicated to establish the diagnosis before making any decision regarding therapy. A fine-needle biopsy may prove to be sufficient, but an 18-gauge needle punch biopsy or an open procedure may be required. Depending on the anatomic location of the mass, an extended substernal mediastinoscopy, anterior mediastinotomy, unilateral video-assisted thoracoscopy, or even lateral thoracotomy may be required. A pleural or pericardial effusion, when present, should be sampled by the appropriate technique; when needle aspiration and cytologic smears fail to yield a diagnosis, video-assisted thoracoscopy may be of value.
Other Diagnostic Evaluations in Patients with a Thymoma
All patients with a suspected thymoma should be evaluated for myasthenia gravis. Any blood dyscrasias accompanying an anterior mediastinal mass should be fully documented. A metastatic evaluation is contraindicated unless symptoms of distant involvement are evident clinically.
Serum levels for -fetoprotein and -human chorionic gonadotropin should be obtained in all young men with a mediastinal mass to rule out the presence of a malignant germ cell tumor. Pragmatically, this testing could be omitted in men with an obvious parathymic syndrome.
 |
Fig. 173-13. A. Posteroanterior radiograph of a predominantly right-sided thymoma. Note the presence of a silhouette sign with obliteration of the ascending aortic shadow. No tracheal distention is present because the lesion is in the anterior compartment. B. Lateral radiograph, same patient. Minimal obliteration of the anterior cardiac window is seen superiorly. C. Radiographic features of a predominantly left-sided thymoma. The silhouette sign is absent, and the aortic knob is clearly seen. D. Computed tomographic scan of same lesions shows normal lung between the thymoma and the aortic knob posteriorly. |
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Treatment
The treatment of a thymoma depends on its clinical presentation, but most important, on whether the thymoma is encapsulated and free from adjacent structures, is fixed to adjacent tissue, or is invasive into surrounding structures on its surgical removal and its subsequent histologic examination for evidence of invasion into or through the capsule into adjacent structures. Surgical excision is the keystone of therapy. Radiation therapy is believed by many to have an essential role in stage II and III disease. Chemotherapy has a secondary role in obvious, locally nonresectable disease or in the presence of distant metastatic spread, both of which are uncommon at original presentation. An increasing amount of evidence, however, shows it has a role as neoadjuvant therapy for initially advanced local disease or in locally recurrent disease before reoperation. Port and Ginsberg (2001) have even suggested that any patient with a thymoma 5 cm or greater in size should be considered a candidate for neoadjuvant chemotherapy before surgical intervention.
Surgical Excision
All patients with thymoma, except those with clinically grossly nonresectable disease or with spread beyond the thorax,
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should undergo as complete a resection of their disease as possible. The presence of an intrapulmonary metastasis should not negate this approach, but the pulmonary lesion should be excised at the same time when it can be accomplished by a lobectomy or less. Whether a pneumonectomy is justified is questionable. In the presence of a pleural or pericardial effusion containing tumor cells with tumor seeding, resection is unjustified. Nakahara and associates (1988), however, have carried out a pleuropneumonectomy and thymectomy in the presence of pleural seeding. Whether this measure is appropriate is unanswered. When pleural seeding or pericardial implants are present without an effusion, resection of implants is justified. The implant and adjacent pleura should be excised widely and down to the endothoracic fascial layer. Whether a pleurectomy is justified when many multiple lesions are present is undetermined. When the pleural implant is situated on the diaphragmatic surface, Port and Ginsberg (2001) recommend that a full thickness of the diaphragm be removed. Closure may be carried out by direct suture repair or insertion of a graft as necessary.
 |
Fig. 173-14. Large right-sided cardiophrenic angle mass that proved to be a benign thymoma on exploration and surgical excision. From Shields TW, Lees WM, Fox RT: Anterior cardiophrenic angle tumors. Q Bull Northwest Univ Med School 36:363, 1962. With permission. |
 |
Fig. 173-15. Lateral radiograph of the chest reveals a mass opacifying the anterior cardiac window. The lesion proved to be a benign thymoma on excision through a median sternotomy. |
In patients with a grossly encapsulated lesion, complete excision, including a total thymectomy, is the procedure of choice. Simple enucleation is to be avoided except under unusual circumstances (i.e., excision through a lateral thoracotomy with an unknown preoperative diagnosis) because a small percentage of patients without myasthenia gravis develop the disease sometime in the immediate or remote postoperative period. In addition, in some apparently encapsulated tumors, as noted by Kornstein and colleagues (1988) and others, microscopic invasion of the capsule occasionally is evident on final pathologic examination.
The preferred approach is a median sternotomy. A posterolateral approach may be necessary for large tumors primarily in one hemithorax or for the lesion that arises infrequently in the anterior cardiophrenic angle. For large midline tumors, Patterson (1992) suggested the use of bilateral anterior fourth intercostal space incisions with transverse section of the sternum (clamshell incision). The use of video-assisted thoracoscopic removal of a thymoma, as reported by Landreneau and associates (1992), is unacceptable, even for stage I disease. In an extended procedure, the entire thymus and adjacent fat, as well as any involved structures, should be removed if possible.
In patients with gross fixation of the tumor to one or more nonvital adjacent structures, resection of the adjacent involved tissue (i.e., pleura, lung, pericardium) should be carried out along with complete excision of the tumor and the residual thymus gland. When one phrenic nerve is involved and a curative resection can otherwise be carried out, it is recommended that excision of the nerve be done if the patient can tolerate the loss of the function of one hemidiaphragm from a respiratory standpoint. This loss may be a problem in the patient with myasthenia gravis, and clinical judgment must be exercised. If both nerves are involved, neither should be excised, and only debulking is performed. When the wall of the superior vena cava is involved in the absence of a clinical superior vena cava syndrome, the surgeon should attempt lateral wall resection or even complete circumferential excision and replacement of the vessel with a spiral saphenous vein graft or an expanded or ringed polytetrafluoroethylene prosthesis. Dartevelle (1987, 1991), Nakahara (1988), Masuda (1988), and Shimizu (1992a) and their colleagues report success with this maneuver when the vein
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has been involved but no obstruction or thrombosis of the vessel is present (Fig. 173-18). Yagi and associates (1996) managed 12 stage IIIa thymomas with superior vena cava or innominate vein involvement by angioplasty, reconstruction, or both. All patients received preoperative or postoperative radiation therapy, or both. Long-term survival occurred in 10 of 12 patients, although two of the patients had subsequent thrombosis of the left innominate vein. Treatment of thymic tumor thrombosis of the superior vena cava and intraatrial extension of the tumor has been reported rarely. Stolf (1982), Fujio (1985), Airan (1990), and Yokoi (1992) and their associates have each reported one such case. Occasional long-term survival has been recorded. Initial multimodality therapy and subsequent complete removal under cardiopulmonary bypass is recommended in such patients.
 |
Fig. 173-16. A. Posteroanterior radiograph of a patient with myasthenia gravis; the mediastinum appears normal. B. Lateral radiograph suggests a small mass is just anterior to the root of the aorta. C. Computed tomographic scan reveals an anterior mediastinal mass, which proved to be an invasive thymoma. |
 |
Fig. 173-17. Computed tomographic scan of a stage III lesion on plane radiography of the chest, which revealed a metastatic pulmonary nodule, thus converting the patient to stage IVB disease. |
When the wall of the aorta, major pulmonary vessels, recurrent nerves, trachea, or other vital structures are involved,
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debulking only is possible. Areas of residual disease should be marked and documented. Some controversy surrounds whether debulking is any more satisfactory than biopsy alone, as noted by Cohen (1984) and Wang (1992) and their colleagues.
 |
Fig. 173-18. Schematic representation of reconstruction of superior vena caval system with ringed polytetrafluoroethylene graft in three patients with invasive thymoma. PA, pulmonary artery; RA, right atrium; SVC, superior vena cava. From Nakahara K, et al: Thymoma: results with complete resection and adjuvant postoperative irradiation in 141 consecutive patients. J Thorac Cardiovasc Surg 95:1041, 1988. With permission. |
Operative mortality is low for resection of a thymoma, whether grossly encapsulated or invasive. Lewis and associates (1987) reported only a 3.1% mortality rate in 227 patients who had total resection of their neoplasms. Bergh and colleagues (1978) reported no deaths in patients with stage I or II disease, but three deaths in 14 patients (21%) with stage III disease, for an overall mortality rate of 7.7%. Shamji and co-workers (1984) reported no operative deaths in 52 patients (25 stage I and 27 stage II tumors). Maggi and colleagues (1991) reported an operative mortality rate of 2.9%; 71% of the deaths were attributed to myasthenic crises. Moore and associates (2001) operated on 77 patients [66 (85%) had macroscopic complete resection], and there was only one postoperative death; this was due to respiratory failure in a patient with myasthenia gravis (1.2%). In Blumberg (1995) and Regnard (1996) and their colleagues' series, the operative mortality rates were 2% and 1.6%, respectively.
Operative morbidity occurs most frequently in patients with myasthenia gravis or with prior cardiovascular disease. Lewis and colleagues (1987) reported a nonfatal complication rate of 39% in their 227 patients who underwent complete resection of a thymoma. Moore and associates (2001) had a complication rate of 25.9% (20 of 77 patients). Regnard and colleagues (1996) reported a morbidity rate of only 6.7%.
Radiation Therapy
Irradiation has had an integral role as a treatment modality in patients with invasive thymoma. Its role in the management of completely encapsulated tumor (stage I) is no longer recommended. Nonetheless, Monden and associates (1985) believe that all patients should receive irradiation after resection, regardless of the postoperative stage. This group reported a 0% recurrence rate in patients who received radiation therapy versus an 8% rate in nonirradiated patients after resection of stage I disease. Most other authors do not recommend this approach because the recurrence rate in stage I disease is low (at most, 8% to 12%), and in many series, such as that reported by Haniuda and co-workers (1992), the recurrence rate was 0%. Therefore, routine radiation therapy in stage I patients is not recommended because far too many patients would receive radiation therapy unnecessarily. A point might be made to irradiate the patients [about 25% in Lewis and colleagues' (1987) series] with gross fixation at operation but no invasion of the capsule microscopically because these authors did note a slight reduction in survival in this subset when compared with those patients with stage I disease with no fixation. Likewise, as previously noted, Regnard and associates (1996) reported five recurrences in stage Ib disease (nontumoral adhesion present), whereas there were none in their stage Ia patients (no adhesions present), as defined in their adaptation of the French GETT classification. However, no other specific data support this suggestion to irradiate this group of patients.
The role of irradiation in patients with completely resected stage II disease is controversial. Batata and associates (1974) reported that the only long-term disease-free survivors with invasive stage II disease were those who had received postoperative irradiation. Masaoka and colleagues (1981) are strong proponents of postoperative radiation therapy in all patients with invasive thymoma whether they have undergone a complete or an incomplete surgical resection. Monden (1985), Nakahara (1988), Karasawa (1990), and Hug (1990) and their associates agree with this therapeutic
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approach. However, Cohen and co-workers (1984) could find no statistical difference in survival in patients with completely resected invasive thymoma with or without the use of postoperative irradiation. Subsequently, Haniuda and associates (1992) reported that postoperative irradiation was of no benefit in patients with stage II thymoma, except possibly in a small subset of patients with stage IIp1 disease (fixation to pleura but no evidence of microscopic invasion). In 1996, Haniuda and co-workers further noted no statistical difference in disease-free survival in their stage II patients with or without the use of adjuvant radiation therapy. Regnard and colleagues (1996) likewise reported no survival benefit with the use of postoperative irradiation. Pan and associates (2001) also suggested that irradiation is unnecessary in stage II patients with either type A or AB thymomas but that it was indicated in those stage II patients with type B1 to B3 thymomas. Mangi and colleagues (2002) at the Massachusetts General Hospital found that the addition of adjuvant radiation therapy did not significantly alter either the local or distant recurrence rates in completely resected stage II thymomas. At 10 years of follow-up, the disease-specific survival rate was 100% in both groups. Recently, Singhal (2003), a member of the University of Pennsylvania group, presented data that likewise support the conclusion that radiation therapy is of no benefit in completely resected stage II thymomas. These additional data have given further support to the decision for discontinuance of the recommendation for postoperative irradiation in completely resected stage II disease. Of additional interest, although unexplained, Ruffini and associates (1997) showed a significant advantage of the occurrence of fewer local and distant recurrences in those stage II patients not receiving irradiation over those that did; the recurrence rates were 4% and 31%, respectively. However, there were only four patients in the irradiated group. One may conclude that now there appears to be strong support not to irradiate patients with completely resected stage II thymomas.
The value of irradiation postoperatively in completely resected stage III disease is unresolved. The same aforementioned authors in favor of postoperative irradiation in patients with originally invasive disease favor its use in all stage III thymomas, whereas those against its use in stage II disease likewise do not favor its use in completely resected stage III thymomas. The absence of value of irradiation was supported by Port and Ginsberg (2001), who reported no difference in the incidence of recurrence or any survival advantage with the use of adjuvant irradiation in stage III thymoma patients. Nonetheless, despite the conflicting results reported, postoperative irradiation is considered the standard of care at the present time in patients with completely resected stage III thymoma; the reason for this is strictly conjectural.
When an incomplete resection, microscopic or macroscopic, of an invasive thymoma has been done, postoperative irradiation is believed to be mandatory. Most would now add chemotherapy to the therapeutic regimen. An example of the value of radiation therapy in this situation is the report of Krueger and associates (1988) in 12 patients with significant local disease (complete resection in only 1, subtotal resection in 7, and biopsy only in 4 patients with stage III disease) who received 30 to 56 Gy. The authors reported local control in 67% and an actuarial 5-year survival rate of 57%.
Few good dose-response data or other data concerning the appropriate radiation therapeutic regimen are available. McKenna and associates (1989) recommend doses of 45 to 50 Gy for areas of suspected microscopic residual disease and doses of 60 Gy or more when possible for the areas of known gross residual disease. They also suggested the use of brachytherapy with radioisotope iodine 125 (125I) seeds placed in areas of gross residual disease at the time of operation.
Myojin and co-workers (2000) at the Massachusetts General Hospital reported, that in a mixed group of stage III patients (i.e., some had thymic carcinoma and some had preoperative irradiation or chemotherapy), they varied the amount of irradiation as to whether there was a close resection, a microscopically positive margin, or the presence of gross residual disease; the radiation doses were 45 to 60 Gy, 54 Gy, and 60 Gy, respectively. The overall survival rates were 71% and 54% at 5 and 10 years, respectively. The 10-year survival rate was 69% for those patients with negative surgical margins and 14% for those with inadequate margins. Finally, Uematsu and associates (1996) suggested entire hemithorax irradiation after complete resection in patients with stage II or III invasive thymoma. They noted fewer relapses after this extensive irradiation than the more restricted irradiation of only the mediastinum. Whether such radical therapy is really necessary is in some doubt. Some support of this concept, however, may be obtained from the report of Ogawa and colleagues (2002). These authors noted in their review of 103 patients who received postoperative irradiation to either the tumor area or to the full mediastinum that such irradiation prevented most local recurrences but was ineffective in preventing pleura-based recurrence when pathologic pleural invasion was present. There were no pleural recurrences in 71 patients without the presence of pleural invasion, but there were 12 pleural recurrences in 32 (37.5%) patients with documented pleural invasion at the time of resection (4 of 10 stage II and 8 of 22 stage III patients). Whether whole hemithorax irradiation would be beneficial is as yet unknown.
Chemotherapy
With the development of cisplatin-based regimens, chemotherapy of advanced thymomas (nonresectable stage III disease or disseminated stage IV disease) is considered by some authors to be acceptable definitive therapy or as neoadjuvant therapy before surgical intervention. Examples of the former are the studies by Fornasiero and associates (1991), in which they reported a 91.8% clinical response rate, 43% of which were complete with a drug regimen of
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cisplatin, doxorubicin, vincristine, and cyclophosphamide, and that of Loehrer and associates (1990), who reported a 70% response rate. Most often, however, use of chemotherapy is considered most profitable in the neoadjuvant setting. Numerous investigations, in the United States as well as Europe and Japan, such as those done by Kirschner (1990), and Macchiarini (1991) and Ohta (1992) and their colleagues, describe early satisfactory results in advanced stage III clinically nonresectable disease. Initial partial response to the chemotherapy is followed by resection, which must be complete to be of value, and additional postoperative irradiation. Rea and associates (1993), who used neoadjuvant chemotherapy in the management of nonresectable stage III and stage IVA disease, reported that complete or partial resection could be carried out in all patients. The surgical resection, complete or incomplete, was followed by additional chemotherapy, irradiation, or both. A median survival time of 66 months, with a 3-year survival rate of 70%, was recorded by their group. Loehrer and colleagues (1997) reported that an intergroup trial of intensive neoadjuvant therapy followed by surgical resection resulted in a 52.5% 5-year survival rate. Venuta and colleagues (1997), using a somewhat similar regimen in patients with stage III or IV cortical or mixed stage III thymomas, reported a 5-year survival rate of 76%. Thus, it is apparent that neoadjuvant therapy before and adjuvant therapy after surgical resection are successful in salvaging a number of patients with initially nonresectable disease. One can justify a complete resection in this situation, but one also can readily question any role of incomplete removal of the residual tumor. This question probably will never be answered.
Hejna and associates (1999) addressed the subject of nonsurgical oncologic treatment (radiation therapy and chemotherapy) either in locally inoperable or metastatic thymoma or as an adjunct to surgery in a review of a total of 51 chemotherapy studies that had been reported with sufficient data to evaluate. Actually, only a minimal number of patients (410) have been reported, most being case reports or phase II trials of advanced disease. Response rates of greater than 50% have been reported in these polychemotherapy trials. These authors concluded that, although the data are sparse, multimodality approaches using induction chemotherapy followed by resection and consecutive radiation have produced highly promising results in terms of resectability and long-term results.
Of interest is the report of Refaely and colleagues (2001) on the use of thermochemotherapy in the treatment of thymic malignancies with pleural spread. Resection of the primary tumor with or without pleurectomy (an extrapleural pneumonectomy was done in one patient), accompanied by intraoperative hyperthermic pleural perfusion (HPP), was carried out in 15 patients. An intrapleural temperature elevated to 40.3 to 43 C was achieved by the HPP. One hundred fifty milligrams (range, 100 to 200 mg) of cisplatinum was added, and the HPP was then continued for a period of 60 minutes. One patient was lost to follow-up, 4 patients died within 36 months, and 10 patients were alive 10 to 70 months after the procedure (4 for more than 60 months). De Bree and coinvestigators (2002) also reported three patients with metastatic pleural disease limited to one hemithorax from a known thymoma (epithelial thymic tumor, stage IVa) who were treated in a similar manner. Intraoperative hyperthermic intrathoracic perfusion chemotherapy using cisplatin and adriamycin at a temperature of 40 to 41 C for 90 minutes was used after the completion of the extrapleural resection of the disease. One patient relapsed in the opposite hemithorax and was subsequently treated by irradiation and a contralateral HPP procedure. All three patients were alive and free of disease after a mean follow-up of 18 months. The eventual results of this form of multimodality therapy remain unknown.
Somatostatin Analogue Therapy
In patients with recurrent, advanced, refractory thymic tumors who no longer respond to chemotherapy, Palmieri and associates (2002) have suggested a combined regimen of a somatostatin analogue and prednisone. For the consideration of the use of this regimen, the tumor must have a positive indium 111 (111In) DTPA-D-Phe-octreotide scan. In a phase II study, the authors enrolled 16 patients: 10 with type B1 to B3 thymomas, 3 with thymic cancers (type C thymoma), and 3 with small cell neuroendocrine thymic tumors (poorly differentiated neuroendocrine tumors). With a relatively nontoxic regimen of a somatostatin analogue octreotide and prednisone they obtained 1 complete response (6%) and 5 incomplete responses (31%); 6 additional patients (37%) exhibited stable disease, and only 4 (25%) showed progression of the disease. The median survival time was 15 months. The eventual role of this regimen in this unfortunate group of patients remains to be seen.
Treatment of Recurrent Local Disease or Distant Metastases
Occasionally, a patient with an original stage I or, more frequently, a completely resected stage II tumor develops locally recurrent disease. As noted previously, this may occur in as many as 12% of noninvasive thymomas, as reported by Lewis and associates (1987). An incidence of 0% to 5%, however, as reported by Kornstein and associates (1988), Verley and Hollmann (1985), and Ruffini and associates (1997), is more common in patients with noninvasive lesions. This recurrence rate is in contrast to the incidence of local recurrence in completely resected invasive lesions. Monden and colleagues (1985) reported a local recurrence rate of 13% in stage II patients who can be assumed to have undergone a complete resection, 8% in patients with postoperative irradiation, and 29% in those who did not receive this adjuvant therapy. Lewis and associates (1987) and Verley and Hollmann (1985) each reported an incidence of 28%, and Kornstein and colleagues (1988) noted an incidence
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of 33% after resection of stage II disease. Ruffini and associates (1997) reported 30 recurrences in a series of 266 totally resected thymomas (11.2%). Recurrences were less after the resection of encapsulated stage I tumors (5%) than after the resection of invasive tumors (20%). The recurrence rate for stages II, III, and IVa were 10%, 30%, and 33%, respectively. The presence of myasthenia had no effect and use of postoperative irradiation was of no benefit in stages II and III. The recurrences were local in 11 patients, distant in 17, and in 2 patients, the sites were unknown. Sixteen patients underwent attempted surgical resection, but it proved to be possible in only 10. Irradiation was used exclusively in 11 patients. The overall 5- and 10-year survival rates were 48% and 24%, respectively. The better results were obtained by complete resection rather than with the use of radiation therapy; the poorest results were with incomplete resection.
A second resection, if at all possible, should be considered in those patients with a recurrence after a complete resection. Kirschner (1990) reported reoperations for recurrent thymoma. In four of these patients, complete removal was possible. Of the original seven patients, four were alive up to 61 months later, but three had residual tumor. Three patients had died at 60 to 100 months, but only one of these had thymoma. Wilkins (1990) also reported reoperation for five recurrent thymomas. The outcome was successful in four of the patients undergoing the second operation. Ohmi and Ohuchi (1990) reported the successful resection of recurrent pleural disease in three patients.
Regnard and associates (1997) reported a series of 28 patients reoperated for a recurrence after a previous complete thymectomy. Initially, of these 28 patients, 4 were stage I, 9 stage II, 12 stage III, and 3 stage IVa. The recurrences were mediastinal, pleural, pulmonary, pericardial, and, in one, located in the scar. Three patients had carcinomatosis. The second resection was complete in 19 of 28 patients. Three postoperative deaths occurred in patients with associated severe myasthenia. Postoperative irradiation or chemotherapy was used in varying numbers in each group. Of the patients with complete resection, the overall 5-year survival rate was 65%. Three second recurrences were observed in these 19 patients. When resection is not possible or the original disease was stage III, irradiation or additional irradiation may be used when possible. Chemotherapy should be considered in these patients, as it should be in patients with distant metastasis. McKenna and associates (1989) and Hainsworth and Greco (1989a) reviewed the literature on this subject. G ldel and colleagues (1989) reported a retrospective study of 22 patients who had received chemotherapy after prior irradiation (12 patients) and as the initial primary treatment of incompletely resected thymomas (10 patients). Various chemotherapy regimens were used, including cyclophosphamide, doxorubicin, vincristine, and prednisone, and these drugs plus bleomycin. Complete remission was accomplished in 5 of 13 patients. Another regimen was cyclophosphamide, vincristine (Oncovin), and prednisone with or without procarbazine; three of five patients had a complete response. The survival rate was 34% at 3 years, and the authors concluded that combination chemotherapy was effective as the first-line postsurgical treatment of incompletely resected thymoma and in the treatment of local or metastatic relapses after irradiation.
Some new regimens suggested by many medical oncologists contain cisplatin as a major component. The early phase II trials, summarized by Hainsworth and Greco (1989b), suggest a number of satisfactory complete response rates. However, in a review of 24 patients, Bonomi and associates (1993) found the use of cisplatin to be of little value. Chahinian (2001) reviewed 14 trials of combination chemotherapy that included cisplatin and 10 trials that did not; the complete response rates were 26% and 35%, respectively, and the partial response rates were 45% and 30%, respectively. Thus, the use of cisplatin appears to be relatively important.
Survival
Certain prognostic features are evident from the various studies reported that affect survival of patients with thymoma. In the reviews by Lewis (1987), Monden (1984), and Verley and Hollmann (1985) and their colleagues, the presence of myasthenia gravis was no longer an adverse factor in the patients with thymoma. In fact, the long-term results of treatment in some series appear to be better in patients with thymomas associated with myasthenia than those with nonmyasthenic thymomas. Early detection in the former probably plays the major role. Crucitti and associates (1992) reported their experience in treating 103 patients with thymoma associated with myasthenia gravis. Extended thymectomy was carried out with an overall operative mortality rate of 4.8%; however, it was less (1.7%) in the patients operated on since 1980. In their series, 42%, 49%, 9%, 3%, and 0% of the patients were in Masaoka's class I, II, III, IVa, and IVb, respectively. The long-term survival rate was 80% at 10 years. The response of the myasthenia appeared not to be dissimilar to that in nonthymomatous patients. Patients with thymomas and red cell aplasia, hypogammaglobulinemia, or systemic lupus erythematosus do poorly regardless of the stage of the tumor.
The invasive nature of a thymoma and whether complete resection could be carried out are the major important factors in all aforementioned series. Cell type played a somewhat adverse role because many of the invasive lesions are predominantly type B3 (epithelial subtype), although Nakahara and associates (1988) reported no relationship of cell type to survival after complete resection and postoperative radiation therapy. Regnard and colleagues (1996), in a series of 307 thymomas, reported overall survival rates of 67% and 57% at 10 and 15 years, respectively. With complete resection, these rates were 76% and 66%. With incomplete resection, the 10- and 15-year survival rates were
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reduced to 23% and 15%, respectively. In this series, radiation therapy appeared to be of no benefit. In a multivariate analysis of factors predicting survival and recurrence after treatment of 118 patients with thymic tumors (75 thymomas and 43 thymic carcinomas), Blumberg and associates (1998) found that the stage of the disease was the only independent prognostic factor affecting recurrence. Independent predictors of long-term survival were the stage, tumor size, histology, and extent of resection. Other findings supported the aforementioned statements relative to the presence of associated diseases and also suggested that the use of irradiation was of little or no effect in patients with stage II or III disease.
The overall survival rate of patients with stage I disease (encapsulated) is between 95% and 97% at 5 years and between 80% and 95% at 10 years. In some series, no drop-off in the number of survivors was noted in subsequent years, but in the series by Verley and Hollmann (1985), a major decrease in survival relative to cell type of noninvasive tumors was observed. Lewis and associates (1987) also noted a major decrease in the survival rate after 10 years in patients with the epithelial variety (type B3) of thymoma.
The survival rate of patients with stage II and III (invasive) tumors is reduced to 60% to 70% at 5 years and to 40% to 50% at 10 to 15 years. The results of combined surgical and radiation therapy reported by Nakahara and colleagues (1988) are somewhat better in patients with stage III and IV disease (Table 173-12). In contrast, the results of Shimizu and associates (1992b) are poorer for patients with stage III or IVa disease. They recorded only 56% 5-year and 14% 10-year survival rates in stage III; in stage IVa, the survival rates were 40% and 0%, respectively.
Venuta and colleagues (1997), who classified their patients with the Marino and M ller-Hermelink (1985) histogenetic classification, reported 8-year survival rates of 94% for the medullary type, stage I and II, and for the mixed type, stage I, managed by radical resection alone; a 100% survival rate for the invasive cortical type, stages I and II, and for the mixed type, stage II, treated by resection and postoperative irradiation; and a 76% rate survival for the cortical type, stages III and IV, and for the mixed type, stage III, managed by neoadjuvant chemotherapy, radical surgery, and postoperative chemotherapy and irradiation. Pich and associates (1995) analyzed their long-term survival for a number of different factors; of these, only those results related to the clinical stage, the traditional histologic features (no longer used), and the histogenetic classification of Marino and M ller-Hermelink (1985) are noted in Table 173-13. Okumura and associates (1999) reported that in 194 patients with epithelial thymic tumors (thymomas) who had undergone complete or only partial resection of their tumor followed by appropriate postoperative therapy, the Masaoka stage and the involvement of the great vessels were the only independent significant prognostic factors. The 10- and 20-year survival rates for these factors are shown in Table 173-14.
Lardinois and colleagues (2000), on the other hand, reported that both the M ller-Hermelink histologic and the Masaoka stage classifications were independent predictors of both overall and disease-free survival in patients with epithelial thymic tumors (Table 173-15). Subsequently, Okumura and associates (2001) reported the clinical and functional significance of the WHO histologic classification of thymic epithelial tumors (thymomas). This was
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based on 140 patients with thymoma. The percentage of invasive tumors in each category was as follows: type A, 12.5%; type AB, 38.6%; type B1, 40%; type B2, 69.4%; type B3, 80%; and type C, 100%. There were three unclassified noninvasive lesions, so that overall, 53% of the lesions were invasive (Table 173-16). All six recurrences at the time of publication occurred with type B2 tumors. Follow-up was short, a median of 3.75 years; thus, long-term survival of the various categories in the WHO classification remains unknown at present.
Table 173-12. Survival Rates in Terms of Surgical Procedures, Stage, and Histologic Type | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Table 173-13. Long-Term Survival of Patients with Thymoma | |||||||||||||||||||||||||||||||||||||||||||||||||||||
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Table 173-14. 194 Epithelial Thymic Tumors: 10- and 20-year Survival According to Masaoka Stage and Great Vessel Involvement | ||||||||||||||||||||||||||||||||||||||
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Table 173-15. Ten-Year Survival Rate after Treatment of Epithelial Tumors of the Thymus | ||||||||||||||||||||||||||||||
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Finally, the major factors relating to long-term survival appear to be complete encapsulation of the tumor, complete removal of the tumor, small tumor size, and cell type, predominantly types A and AB. Postoperative irradiation of invasive tumors may or may not be beneficial in regard to long-term survival. Conversely, adverse factors for survival are an invasive tumor, an incomplete resection, a large tumor size, and a predominantly type B thymoma (epithelial cell type).
COMBINED THYMOMA AND THYMIC CARCINOMA
A number of investigators, as noted during the 1990s, have identified thymic tumors that appear to blend in varying degrees the microscopic features of an epithelial, most often a cortical histogenetic type, thymoma and those of a well-differentiated squamous cell carcinoma. Among these investigators are Kirchner (1992) and Quintanilla-Martinez (1994) and their associates, as well as Shimosato (1994) and Suster and Moran (1996). A few of these tumors are combined with a poorly differentiated squamous cell carcinoma, and some are of the spindle cell type. These tumors are now placed in the type B3 tumors in the WHO classification. Suster and Moran (1999) refer to these tumors as atypical thymomas or moderately differentiated thymomas. Myasthenia gravis is present in only a few of the patients, and most of the tumors are invasive in nature. Complete resection and postoperative irradiation have been suggested as the treatment of choice.
Suster and colleagues (1997) have added another variety to this potentially new category of thymic tumors. This has been described as a thymoma with pseudosarcomatous stroma, which may simulate a carcinosarcoma. The epithelial cells are positive for keratin and epithelial membrane antigen, whereas the spindle cells react for vimentin and actin. Clinically, these lesions behave as relatively benign invasive tumors. Resection and postoperative adjuvant therapy would appear to be indicated.
THYMIC CARCINOMAS (TYPE C THYMOMAS)
Thymic carcinomas are a small group of epithelial tumors characterized by malignant cytologic and architectural
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features. In addition to squamous cell carcinoma and lymphoepithelioma-like carcinoma, Snover and colleagues (1982) described five distinct histologic variants; Tanaka and associates (1982) subsequently also described a mucoepidermoid variant. Matsuno and colleagues (1998) recorded a heretofore not described papillary adenocarcinoma of the thymus that belongs to this category of tumors. Choi and associates (2003) reported the occurrence of a papillary adenocarcinoma as well as a mucinous subtype of an adenocarcinoma. These authors noted that nine cases of adenocarcinoma of the thymus (including their two cases) had been published in the literature. Most of these were seen in association with a thymic cyst or a type A thymoma. At present, the thymic carcinomas are divided into two categories: low-grade and high-grade malignant tumors (Table 173-17). Rosai (1999) separates the squamous cell tumors into epidermoid keratinizing and nonkeratinizing cell types. Most of the thymic carcinomas are curiosities. Only the squamous cell carcinoma and the lymphoepithelioma-like carcinoma varieties are of major clinical significance; even then, these two types are rare. A report by Hartmann and associates (1990) recorded fewer than 100 cases of thymic carcinomas described in the literature. In his text, Kornstein (1995) reviewed a total of 122 cases presented in six selected series: Suster and Rosai (1991), and Shimosato (1977), Snover (1982), Wick (1982a), Kuo (1990), and Truong (1990) and their colleagues. Hsu and associates (1994) reported an additional 20 cases. Of the total of 144 cases, 16 were small cell carcinomas, and 2 were carcinoid tumors. Most authors believe that these latter two types more properly belong in the category of neuroendocrine tumors. Of the total 126 cases remaining, pure squamous cell tumors made up 31.9% of the total, and lymphoepithelioma-like carcinomas made up 29.3%. Basaloid and mucoepidermoid tumors represented 3.9% and 2.3%, respectively, of the total. Clear cell tumors and sarcomatoid tumors each represented 4.7%, and the undifferentiated, mixed tumors and others of high-grade malignancy made up 23.8%. Thus, about one third of the thymic carcinomas are of low-grade malignancy, and two thirds are of high-grade malignancy. Of major interest is that few, if any, of the patients with low-grade tumors die of their disease, whereas more than 85% of those with high-grade tumors do so.
Table 173-16. Clinical Stage and the Incidence of Invasive Tumors According to the World Health Organization Classification | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Table 173-17. Thymic Carcinomas | ||||||||||
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The staging of thymic carcinoma is not standardized. Yamakawa and colleagues (1991) have suggested that a TNM classification for thymic carcinomas is of value and is applicable in predicting the prognosis. On the other hand, Blumberg and colleagues (1998), in evaluating 43 patients with thymic carcinoma, showed that the use of the staging system of Masaoka for thymomas had no value, which parenthetically is not surprising when one considers the differences in these two types of tumors. The aforementioned authors did find that invasion of the innominate vessels was associated with a poor prognosis. Hsu and associates (1994) also noted that the extent of the disease at the time of diagnosis was the most valuable factor in predicting the patient's survival.
Squamous Cell Carcinoma
Squamous cell carcinoma is the most common variant of the thymic carcinomas. In the number of cases reported,
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squamous carcinoma of the thymus is more often seen in men than in women and most commonly affects persons in the sixth decade of life. Grossly, the tumor is partially encapsulated and has the appearance of an invasive thymoma. The low-grade, well-differentiated tumors remain localized, whereas the high-grade, poorly differentiated tumors have a propensity to spread to the anterior mediastinal lymph nodes and to extend into the pleura, lungs, and pericardium.
Histologically, the tumor resembles a typical squamous cell carcinoma (Fig. 173-19). It may rise de novo or develop in a preexisting thymoma. The well-differentiated tumor may be locally invasive but has prominent lobular growth, and necrosis is not often apparent. The poorly differentiated squamous cell tumor shows little lobular growth, is infiltrative, and is aggressive locally and also may metastasize widely. The patient presents with weight loss, chest pain, cough, and hemoptysis. Radiography reveals a well-defined anterior mediastinal tumor.
Treatment consists of surgical resection when possible. Lucchi and associates (2001) recommend neoadjuvant chemotherapy in all thymic carcinomas before surgical intervention. The tumors are sensitive to irradiation, which may be indicated even if the tumor has been completely removed. If the lesion is nonresectable or is only partially excised, irradiation is definitely warranted. Shimosato and colleagues (1977) reported an 11-year disease-free interval in one patient with radiation therapy after only an exploratory thoracotomy. Hainsworth and Greco (1989a, 1989b) have used combination chemotherapy (cisplatin, vinblastine, and bleomycin) for undifferentiated mediastinal carcinomas; perhaps this regimen might be useful in patients with recurrent or metastatic squamous cell carcinoma of the thymus.
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Fig. 173-19. Histopathologic features of thymic carcinoma (cytologically malignant) (hematoxylin and eosin, original magnification 640). Tumor cells of this squamous cell carcinoma of the thymus are large with indistinct borders; nuclei are vesicular with prominent nucleoli and numerous mitotic figures. |
The infiltrating squamous cell tumors arising in the thymus must be differentiated from squamous cell tumors arising from the lung. Fukai and associates (1995) report the use of immunohistologic staining with monoclonal antibodies to cytokeratins 7 and 13 to be helpful in this regard; the ones originating in the thymus were positive for these substances, whereas those from the lung were not.
The prognosis of the well-differentiated squamous cell tumor is excellent when recognized early in the course of the disease. The prognosis for the poorly differentiated tumors is poor, regardless of the time of discovery.
Lymphoepithelioma-like Carcinoma
Lymphoepithelioma-like carcinoma has morphologic features identical to those of lymphoepitheliomas of the nasopharyngeal area. The tumor is composed of solid sheets of epithelial cells with open nuclei and indistinct cytoplasm admixed with prominent lymphoid infiltrates. Henle and Henle (1976) reported that lymphoepitheliomas have elevated titers of Epstein-Barr virus, and Leyvraz (1985) and Dimery (1988) and their colleagues described similar cases. Treatment is controversial. Some believe that, as with nasopharyngeal lesions, treatment should consist of radiation therapy once the tissue diagnosis is obtained. Dimery and associates (1988) reported a patient successfully treated with chemotherapy; the primary drugs used were cyclophosphamide, doxorubicin, cisplatin, and prednisone. Treatment intensification and adjuvant irradiation of the tumor bed were added after an excellent initial response. The future role of chemotherapy in the treatment of lymphoepithelial tumors of the thymus is as yet undetermined. The second option is neoadjuvant chemotherapy plus surgical excision. Which option will lead to a better result remains unknown.
TUMORS OF NEUROENDOCRINE CELL ORIGIN
Three tumors thymic carcinoid, atypical carcinoid, and small cell carcinoma of the thymus are placed in the category of tumors of neuroendocrine cell origin because of their neuroendocrine differentiation. Their origin may be from the argyrophil cells in the normal thymus. Their relationship to Kulchitsky's cells of neural crest origin is in some doubt, and the possibility is that these cells are related to amine precursor uptake and decarboxylation cells of endodermal D cell origin in the digestive tract. The studies of
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Sidhu (1979), Carstens and Broghamer (1978), Alvarez-Fernandez (1980), and Wick and Scheithauer (1982) support this concept of origin. Despite their distinct histologic and immunologic characteristics, Kirchner and M ller-Hermelink (1989) believe that these are a subset of thymic carcinoma and should be classified as such. Nonetheless, because of the distinctive features of these tumors, they are considered as a separate entity. Moran and Suster (2000a) believe these lesions should be termed thymic neuroendocrine carcinomas. The three varieties may be referred to as (a) low-grade (well-differentiated, thymic carcinoid); (b) intermediate-grade (moderately differentiated, atypical carcinoid); and (c) high-grade (poorly differentiated, small cell carcinoma) thymic neuroendocrine carcinomas. In this chapter, these terms are used interchangeably with the older terminology for these thymic tumors.
These three tumors may be only histologic variants of the same cell type as documented by their morphologic, ultrastructural, and immunohistochemical characteristics; their ability to produce biochemical substances associated with the amine precursor uptake and decarboxylation cells elsewhere in the body (note that most of the foregut amine precursor uptake and decarboxylation tumors are deficient in the aromatic amino acid decarboxylase enzyme necessary for the conversion of 5-hydroxytryptamine to serotonin), and their clinical behavior. Further support is given by the observation of Wick and Scheithauer (1982) of a small cell carcinoma arising in transition from a thymic carcinoid.
Well-Differentiated and Moderately Differentiated Thymic Neuroendocrine Carcinomas
Three bronchial adenomatous (carcinoid) tumors were described by Ringertz and Lidholm (1956) in the anterior mediastinum; two were believed to be benign, and one was malignant. The significance of these lesions was not recognized, and it was not until the report of Rosai and Higa (1972) that the true nature of these lesions was realized. These authors described eight cases and summarized the eight previous cases in the literature. They defined these carcinoid tumors as separate thymic neoplasms and pointed out the distinctly different histologic, electron microscopic, and clinical features that separated these tumors from the true epithelial tumors of the thymus. Numerous other reports relative to these tumors have been presented by Gartner and Voorhess (1993) and Wick (1980), Herbst (1987), Economopoulos (1990), Wang (1994), Valli (1994), and de Montpr ville (1996) and their associates. In addition, Moran and Suster (2000b) published a clinicopathologic analysis of 65 cases (29 low-grade, well-differentiated and 36 intermediate-grade, moderately differentiated tumors); 15 high-grade tumors (small cell carcinomas, poorly differentiated) were also included in their report. Moreover, many single cases have been noted in the various series of thymic carcinomas. Also, as noted subsequently, numerous reports relative to the thymic carcinoid association with various endocrinopathies also have been published.
Pathology
Grossly, carcinoids of the thymus (both the well-differentiated and moderately differentiated thymic neuroendocrine carcinomas) are most often large, and one half of the lesions may be infiltrative into adjacent structures. In a few patients, the tumor may be small and inconspicuous. This is observed more often in patients with associated Cushing's or other paraneoplastic endocrinopathies, but even so, a small lesion is a relative rarity.
On light microscopy, carcinoid tumors of the thymus demonstrate the classic histologic features of carcinoid tumors elsewhere in the body and may be divided into typical and atypical varieties, the latter being the more common. Suster and Moran (2001) described the histologic features of these neuroendocrine tumors of the thymus. The well-differentiated (carcinoid) tumors most often show one of two growth patterns: (a) a nested (Zellballen) pattern, or (b) a trabecular pattern. The tumor cells have small round nuclei with coarse clumping of chromatin surrounded by abundant acidophilic cytoplasm. Subtle features of atypia may be identified. Foci of necrosis with dystrophic calcification may be present. Six unusual growth patterns may be seen infrequently: (a) an oncocytic variant; (b) a spindle cell variant; (c) a pigmented (melanotic) variant; (d) a mucinous stroma variant; (e) a pseudoangiomatous appearance; and (f) an amyloid-like stroma variant. These variants behave no differently from the other well-differentiated tumors but do result in difficult diagnostic problems in differentiating these tumors from other nonneuroendocrine tumors that may occur in the anterior mediastinum. The moderately differentiated neuroendocrine (atypical carcinoids) tumors may show similar growth patterns, but there is a greater tendency to form sheets of tumor cells. The formation of large clumps ( balls ) of tumor cells with central areas of necrosis is common. There is commonly the formation of small acinar or rosette-like structures with empty lumens. Marked cellular atypia and frequent mitotic figures are prominent (Table 173-18). The poorly differentiated neuroendocrine tumors (small cell carcinomas) are composed of sheets or cords of highly atypical, small round blue cells. A large cell form also has been described by Chetty and associates (1997). Extensive areas of necrosis and a high mitotic index are constant features in these poorly differentiated tumors (see Table 173-18).
On electron microscopy, the characteristic dense-core, neurosecretory granules are present. On immunohistochemical studies, various amines may be demonstrated. Immunoreactive adrenocorticotropic hormone (ACTH) is found most frequently, and although these cells are not supposed to produce serotonin, Wick and Scheithauer (1982) reported identifying this substance in two cases. Kornstein (1995) and Moran and Suster (2000a, 2000b) have summarized
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the immunohistochemical findings in these tumors. These studies reveal positive reaction to antibodies for CAM 5.2 low-molecular-weight cytokeratins, chromogranin, neuron-specific enolase, synaptophysin, broad-spectrum keratins, and Leu-7. A number of peptides in addition to ACTH also have been found in these tumors. These are calcitonin, cholecystokinin, gastrin, somatostatin, and -endorphin. These immunohistochemical reactions are helpful in differentiating thymic carcinoids from lymphoproliferative disorders as well as from thymomas.
Table 173-18. Thymic Neuroendocrine Tumors: Terminology and Cytologic Features | |||||||||||||||||||||||||
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Clinical Features
More than two thirds to three fourths of patients with thymic neuroendocrine carcinomas are men. The mean age of the 15 patients reported by Wick and associates (1982b) is 42 years. This median of age has remained the same with the additional cases in the literature. Of some interest is that Gartner and Voorhess (1993) identified only eight patients younger than the age of 17 years with a thymic carcinoid tumor reported in the literature; they presented one additional case in an adolescent. One third of all patients may be asymptomatic, and the lesion may be discovered only on a routine chest radiography. Most patients, however, have either local or constitutional symptoms or signs, or both. Local symptoms of pain in the anterior chest, cough, dyspnea, and superior vena cava syndrome are common. Occasionally, fatigue, fever, and night sweats are present. Rarely, clubbing and musculoskeletal complaints are noted. About one fourth to one third of patients with a thymic neuroendocrine carcinoma have features of an endocrine abnormality. Cushing's syndrome is the result of ectopic ACTH production by the tumor; this activity may be intermittent in nature, as noted by Thorner and associates (1982), Gartner and Voorhess (1993), and others. Men and women are affected about equally when this is the only endocrinopathy present. Most patients are in the fourth or fifth decade of life. It is of interest that all nine patients younger than 17 years of age with thymic carcinoids reviewed by Gartner and Voorhess (1993) had associated Cushing's syndrome. The patients with thymic neuroendocrine carcinomas and Cushing's syndrome also may present with complete or partial multiple endocrine neoplasia (MEN) syndrome. Endocrine neoplasia syndrome also may be present in the absence of Cushing's syndrome.
Cushing's Syndrome
Thymic carcinoids, as well as pulmonary carcinoids, infrequently may be associated with ectopic Cushing's syndrome. Moran and Suster (2000b) reported an incidence of 6% in their study. Other endocrine abnormalities were present in 18% of the patients.
Once the ectopic nature of the Cushing's disease is established by exclusion of a pituitary adenoma, adrenal adenoma or hyperplasia, or some other ectopic site, the thorax should be investigated for either a pulmonary or thymic carcinoid. In most situations, the thymic tumor is readily detected, but on infrequent occasions, the carcinoid tumor is quite small and may easily be undetected by standard radiographic studies. Helical CT of the chest followed by high-resolution CT of any suspicious area is then indicated. If a lesion is not found or is indeterminate, an octreotide radiolabeled scan (111In-DTPA), as suggested by Fernandez-Fernandez (1997) and Lin (1999) and their associates, should be done. This study is positive in more than 80% of cases. At times, as suggested by Lin and colleagues (1999), a technetium 99m methoxyisobutylisonitrile scan may be used to demonstrate ACTH-producing tumors.
Grossly, the lesions may vary in size from 5 cm to greater than 10 cm in size. Capsular invasion is common, and lymph node involvement and occasional distant metastases may be present at the time of diagnosis. Most often, these thymic carcinoids are of the atypical type (moderately differentiated thymic neuroendocrine carcinoma). Adrenocorticotropin may immunohistochemically stain positive, or it may be negative even in the presence of Cushing's syndrome according to de Perrot and colleagues (2002b). These latter authors reviewed 23 cases in the literature and added 2 of their own. Wick (1980) and Wollensak (1992) and their associates have noted that other cases may have been published but probably were unrecognized as such at the time.
The symptoms of Cushing's syndrome may vary, and infrequently, cutaneous hyperpigmentation is observed. Complete
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surgical resection is indicated if at all possible, even if adjacent structures need to be resected as well. De Perrot and associates (2002b) discussed the necessity of parenteral glucocorticoid therapy perioperatively until normal pituitary secretion has returned. Unfortunately, the prognosis for these patients is poor even with complete resection. Most present with recurrent or metastatic disease within 5 years, and most die within 10 years. Radiation therapy may be of some benefit as a palliative measure.
Multiple Endocrine Neoplasia (MEN) Syndrome
In addition to the aforementioned patients, another 15% to 18% of patients with a thymic carcinoid with or without Cushing's syndrome have an accompanying complete or partial MEN syndrome. Almost all of these latter patients are men, and the most common MEN syndrome is type I (Wermer's syndrome, or multiple endocrine adenomatosis type I). One or more of the following endocrine lesions may be present: single or multiple parathyroid adenomas, islet cell tumors of the pancreas, pituitary adenoma, and, infrequently, an adrenal neoplasm, thyroid adenoma, or multiple lipomas. Rosai and colleagues (1972) and Manes and Taylor (1973) were among the first investigators to note this association. Zeiger and associates (1992) have reviewed the literature and presented their one case. In all, there were a total of 23 cases at that time. De Montpr ville and co-workers (1996) added another case in their review of 14 thymic carcinoids. A few patients present with a MEN II syndrome (Sipple's syndrome). In this syndrome, medullary carcinoma of the thyroid, pheochromocytoma, and parathyroid neoplasia or enlargement may be present. Marchevsky and Dikman recorded the occurrence of this latter syndrome in 1979.
The thymic neuroendocrine carcinomas associated with these endocrinopathies, particularly when a MEN syndrome is present, tend to be more malignant in their behavior, and even though one third of the patients may survive 5 years if a complete resection is carried out, all of the patients have eventually died of their disease. Irradiation and chemotherapy appear to be of little or no benefit in this group of patients. Pass and co-workers (1990) have discussed the medical management of these individuals. Metyrapone may be used to attempt to control the hypercortisolism, as may the more newly developed somatostatin analogues. Inappropriate antidiuretic hormone secretion has been observed in an occasional patient with a thymic carcinoid, as reported by Levine and Rosai (1976) and also as noted in Economopoulos and colleagues' (1990) review. The carcinoid syndrome that may be present in up to 12% of patients with a pulmonary carcinoid tumor, according to Harpole and associates (1992), has been recorded only rarely (0.6%) in patients with thymic carcinoids (thymic neuroendocrine carcinomas), as noted by Soga and associates (1999) in their review of 341 mediastinal and thymic carcinoids in the literature.
Radiographic Features
Radiographically, the locally symptomatic tumor appears as a solid, lobulated, anterior mediastinal mass. Focal stippled calcification occasionally is seen in the mass. CT scans may show extensive infiltration with frequent involvement of the superior vena cava. In patients presenting with Cushing's syndrome or other paraneoplastic endocrinopathies, the tumor at times may be small and not identified on the standard chest radiography. In these patients, CT scans of the chest may demonstrate an unsuspected lesion in the thymus. Brown and associates (1982) reported failure to visualize a thymic carcinoid associated with ACTH production by standard chest radiography in four of five patients, but the tumor was identified by CT scan in the two patients who underwent the examination. In an addendum to their report, the authors noted that CT examination identified the thymic tumor in a sixth patient. Jex and associates (1985) reported that 2 of 25 patients (8%) with Cushing's syndrome from ectopic ACTH-secreting tumors had a thymic carcinoid that was discovered only by CT examination of the chest. In both patients, previous transsphenoidal hypophysectomy and bilateral adrenalectomies had been done without amelioration of the syndrome. Both patients were relieved of the syndrome after excision of the thymic carcinoid. One patient subsequently died of metastatic disease; the other patient continued to be asymptomatic. CT also may be valuable in identifying evidence of recurrence not seen on the radiograph after initial treatment.
Diagnostic Studies
In addition to the aforementioned studies, skeletal survey radiography and radionuclide bone scans should be done when the diagnosis is established either by resection or biopsy. About one third of patients have demonstrable skeletal metastases documented by these studies.
Treatment
Complete surgical resection or even debulking of extensive tumors is advocated by Wick and associates (1982b) at the Mayo Clinic. Radiation therapy has been used postoperatively, but seven of nine patients so treated at the Mayo Clinic developed progressive metastases. Thus, the efficacy of irradiation remains in question. Adjuvant chemotherapy has not been shown to be of benefit.
Prognosis
Wick and associates (1982b) reported that 73% of their patients developed local recurrence or metastases; however, the clinical course may be prolonged despite the evidence of metastatic disease. The overall cure rate is low, and only 13% of the patients followed for at least 5 years by the aforementioned
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authors were alive. In one patient, late metastatic disease was discovered 10 years after initial treatment. The mean survival after diagnosis of metastatic disease in their patients was 3 years. Fukai and colleagues (1999) stressed the point that, even in well-differentiated neuroendocrine tumors (typical carcinoids), it is very difficult to predict their malignant potential by either the T or N status or the histologic grade of the tumor. Even after a complete resection, distant metastases are common (76% of 13 patients). The common sites of metastases were the cervical lymph nodes and the skeletal system. The lung and pleura were likewise relatively common sites, although involvement of the liver, spleen, or brain also may occasionally occur.
In Moran and Suster's (2000b) study, 50% of the 29 patients with low-grade lesions were disease free at 5 years, but only 9% were so at 10 years. Of the 36 patients with intermediate-grade lesions, only 20% were disease free at 5 years, and none were disease free at 10 years. Compared with pulmonary neuroendocrine tumors, those of the thymus are much more aggressive and lethal in their course.
A poor prognostic feature, regardless of the extent of the local disease, is the presence of an associated endocrine syndrome, as noted in the section on Clinical Features. The explanation for this correlation is not known.
Poorly Differentiated Thymic Endocrine Carcinoma
Small (Oat) Cell Carcinoma of the Thymus
High-grade, poorly differentiated thymic neuroendocrine carcinoma [small (oat) cell carcinoma] is a variant of the neuroendocrine tumors of the thymus and is uncommon; only a relatively small number of well-documented examples have been reported. Most have been recorded in the various series of thymic carcinomas, such as in the report of Moran and Suster (2000b), who recorded 15 cases. A small number of patients have been reported by Galanis and associates (1997) as having a primary small cell carcinoma arising in the anterior mediastinum. Eight of 81 patients (9.8%) reported to have a primary extrapulmonary small cell carcinoma were considered in this category; five cases were believed to originate in a lymph node and three from ectopic thymic tissue. The true origin of these latter, poorly differentiated thymic neuroendocrine carcinomas remains unknown, but a thymic origin is not inconsistent.
Patients with small cell carcinoma of the thymus have been managed by resection, irradiation, and adjuvant chemotherapy. Galanis and associates (1997) reported a 13% 5-year survival rate. Exclusion of another primary site, primarily in the lung, must be established. Histologically and by electron microscopy, these tumors resemble the typical small cell cancers occurring elsewhere. Neurosecretory dense-core granules are usually demonstrable. As noted by Rosai and associates (1976) and Wick and Scheithauer (1982), differentiated areas of carcinoid tumor can be found in these tumors.
Small cell, poorly differentiated neuroendocrine thymic carcinomas are aggressive and may metastasize extensively. These tumors often are associated with endocrine neoplasms of various organs (MEN I syndrome). Oyaizu and colleagues (2001) reported the occurrence of a Lambert-Eaton myasthenic syndrome associated with a small cell carcinoma in the anterior mediastinum that possibly developed in ectopic thymic tissue adjacent to the thymic gland.
Treatment consists of chemotherapy with or without irradiation. Resection may be attempted. Several instances of prolonged remission after chemotherapy have been reported by Wick and Scheithauer (1982) and Rosai and associates (1976). Current treatment appears to be surgical resection plus a multiple chemotherapeutic drug regimen and thoracic irradiation for the complete responders, as is in vogue for stage Ia small cell carcinoma of the lung. Survival is poor, and no patients were free of the disease after 5 years in Moran and Suster's report (2000b).
THYMOLIPOMA
Incidence
Thymolipomas, initially described by Lange (1916), have been reported by various authors, such as Dunn and Frkovich (1956), Korhonen and Laustela (1968), and Almog (1977), Ringe (1979), and Otto (1982) and their colleagues. These lesions account for 2% to 9% of all thymic neoplasms. Teixeira and Bibas (1989) reported that thymolipomas accounted for 1.1% of all solid mediastinal tumors. Moran and associates (1995b) reviewed 33 cases of thymolipomas. The ages of their patients ranged from 2 to 64 years, with a mean of 33 years. Their cases were almost equally divided between men and women.
Clinical Features
One half of these patients are asymptomatic, with the lesion being discovered on routine chest radiography. The other half present with symptoms related to compression of the lower respiratory tree (e.g., cough, dyspnea, and, occasionally, hemoptysis). Some patients present with paroxysmal atrial tachycardia.
Infrequently, a thymolipoma has been associated with a systemic disease state. Otto (1982), Reintgen (1978), Le Marc'hadour (1991), and Verbist (1997) and their colleagues reported association of thymolipomas with myasthenia gravis in a small number of patients. Rios-Zambudio and associates (2001) collected 15 cases reported in the English-speaking literature from August 1987 to August 2000 and added three new cases of their own. The cases they listed in
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addition to the previously noted authors were published by Mikkelsen (1986), Alfaro (1989), and Pan (1988), Olanow (1982), Toyama (1995), Sirpal (1995), and Takamori (1997) and their colleagues. Moran and co-workers (1995b) presented two cases among 33 patients with thymolipomas, but no data were presented relative to their two cases with associated myasthenia gravis. Two features were observed in the other 16 patients: (a) the patients with myasthenia gravis were older than average patients without associated myasthenia gravis, and (b) the thymolipomas were markedly smaller in patients with myasthenia gravis than in those without myasthenia gravis. The ages of the patients ranged between 29 years and 63 years; 75% of the patients were 50 years of age or older. The gender distribution was essentially equal. After complete resection of the tumor, improvement in the patients' myasthenia was noted in all cases, with a complete remission in one patient. Despite the improvement noted, the relationship between the thymolipoma and myasthenia gravis remains unknown.
Graves' disease also has been occasionally associated with a thymolipoma. Benton and Gerard reported a case in 1966, and several other cases have been recorded, often associated with myasthenia gravis, such as those by Alfaro (1982) and Pissarra (1995) and their colleagues. Tokitsu and associates (1997) reported one case of associated Graves' disease without the association of myasthenia gravis. The mechanism of these diseases in patients with a thymolipoma remains obscure.
Barnes and O'Gorman (1962) reported an association with aplastic anemia, although the fatty replacement in the thymus may have been the result of ACTH therapy. McManus and associates (1994) reported the occurrence of red cell aplasia, hypogammaglobulinemia, and lichen planus in a patient with a large thymolipoma.
 |
Fig. 173-20. A radiograph of large thymolipoma overriding both sides of the heart, simulating massive cardiomegaly. From Marchevsky AM, Kaneko M: Surgical Pathology of the Mediastinum. New York: Raven, 1984. With permission. |
Radiographic and Computed Tomographic Features
Characteristically, a thymolipoma presents as a large anterior mediastinal mass that, as it enlarges, spreads into the adjacent visceral compartment with a bilobular shape that overrides both sides of the heart (Fig. 173-20). In the series of Rosado-de-Christenson and colleagues (1994), 81% of the thymolipomas were in the inferior portion of the anterior mediastinum, and 18% were in the superior portion of the anterior superior mediastinum. Radiographically, these tumors are difficult to distinguish from other mediastinal masses, pleural or pericardial lesions, basal atelectasis, or even a massively enlarged heart. Almog (1977) and Roseff (1958) and their colleagues presented several patients in whom the thymolipoma simulated such cardiomegaly, and they noted that as many as 40% of thymolipomas may mimic cardiomyopathy on radiologic study. Teplick and associates (1973) stress the characteristically more lucent edges of the mass as opposed to the more opaque borders of an enlarged heart. They believe this feature should alert the observer to the possible correct diagnosis. Moreover, in a well-penetrated Bucky's radiograph, the decreased density of the fatty tissue allows recognition of the true cardiac border and the diaphragmatic leafs.
CT scanning is the most accurate diagnostic technique because adipose tissue has a characteristic coefficient of attenuation that can be identified and quantitated by this method (Fig. 173-21). Faerber and associates (1990), among others,
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have described in detail the CT characteristics of thymolipomas. Rosado-de-Christenson and colleagues (1994) demonstrated two different patterns on CT. The more common pattern showed equal amounts of fat and soft tissue attenuation, whereas the less common pattern demonstrated a predominance of fat attenuation with tiny internal linear foci of soft tissue attenuation. However, the CT attenuation number of a thymolipoma is higher than that of a pure lipoma and might be in the range observed with a liposarcoma. Thus, the CT cannot be absolutely diagnostic, and a tissue biopsy may be necessary to confirm the suspected diagnosis. Of the 27 patients Rosado-de-Christenson and colleagues (1994) reviewed, magnetic resonance (MR) images were obtained in two patients. The MR images showed high signal intensity on T1-weighted spin echo images with areas of intermediate signal intensity. The intensities corresponded to those of subcutaneous fat and skeletal muscle. As noted by Shirkhoda and colleagues (1987), MR imaging can readily discriminate between fat and the blood flowing within the heart chambers, but MR imaging is an unnecessary examination in most cases of thymolipoma.
 |
Fig. 173-21. Computed tomographic scan of thymolipoma (TL) readily identifying its bilobar shape and different attenuation value from that of the surrounded heart. From Marchevsky AM, Kaneko M: Surgical Pathology of the Mediastinum. New York: Raven, 1984. With permission. |
Pathology
Thymolipomas vary greatly in size but tend to be large. They are well encapsulated and resemble an enlarged thymus as a bilobed structure with a partial, superior connection between the two lobes.
The tumor is soft, lobulated, and yellowish tan. On microscopic examination, it is composed of large lobules of mature adipose tissue interspersed with islands of thymic tissue. These lesions are benign. Although adherence to adjacent mediastinal structures may be present, invasion of adjacent structures is not noted. Compression, however, may be present because of the size and location of the tumor.
Treatment
Surgical excision is curative. This may be accomplished through a median sternotomy in almost all patients. Recurrence or malignant transformation has not been reported. The prognosis after surgical excision is excellent.
THYMOLIPOSARCOMA
Havlicek and Rosai (1984) reported one case, and added a second in an addendum, of a liposarcoma associated with thymic tissue. The tumor in the reported case recurred a long time after initial surgical resection. It was composed of both pleomorphic and well-differentiated liposarcoma, which pushed aside the normal thymic elements. Local control was obtained by a second surgical procedure plus adjuvant postoperative irradiation. However, hematogenous metastases occurred subsequently to a vertebral body.
MISCELLANEOUS TUMORS OF THE THYMUS
Thymic Hemangioma
Thymic hemangiomas are rare. Papagiannopoulos and associates (2000) reported a single case associated with a left-sided pleural effusion. A chest radiograph suggested the presence of a lobulated anterior mediastinal mass that was confirmed by CT examination. A preoperative diagnosis was not obtained despite numerous studies. The mass and adjacent thymus were resected. Microscopically, a large number of thick-walled vessels and areas of small capillary channels associated with mature fat, fibrous bands, and areas of cystic degeneration and granulation tissue were present; residual thymic tissue was evident in the mass. The final diagnosis was that of a thymic hemangioma. The authors were able to find three reports, one each by Cohen (1987) and Bertelsen (1975) and their associates, and Niedzwiecki and Wood (1990), in which six thymic hemangiomas were mentioned but with insufficient data for analysis. Whether a thymic hemangioma is a true entity or just a hemangioma located in the gland remains a question.
Neuroblastoma and Ganglioneuroblastoma of the Thymus
Talerman and Gratama (1983), as well as Hutchinson (1968), Asada (1996), and Argani (1997) and their colleagues, have identified five adult patients in whom either a neuroblastoma or a ganglioneuroblastoma was present in the anterior mediastinum associated with thymic tissue (see Chapter 189). These malignant lesions had the typical histologic, electron microscopic, and immunohistochemical features, when immunohistochemical analysis was done, of the malignant sympathetic ganglionic tumors. Argani and associates (1997) noted that these thymic neuroblastomas and ganglioneuroblastomas were negative for cytokeratin but were positive for chromogranin, synaptophysin, and neuron-specific enolase. The histogenesis of these tumors is unknown, but Argani and colleagues (1997) do not believe they are related to the neuroendocrine cells of the thymus because the cells of these neurogenic lesions are negative for cytokeratins, in contrast to the cells of thymic neuroendocrine carcinomas, which are positive. Alternatively, they postulate that the cell origin might be the precursors of the thymic epithelial cells that have undergone neural differentiation. Clinically, these neurogenic tumors of the thymus, if indeed they are thymic tumors, occur in older adults (age
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range, 51 to 80 years), often may be associated with inappropriate antidiuretic hormone secretion, and possess varying degrees of aggressive malignant behavior. Surgical resection is indicated when possible. Essentially, however, the outlook is grave.
Primary Malignant Melanoma of the Thymus
Ohta and associates (1996) reported what they believed to be a primary malignant melanoma of the thymus. No other primary site could be identified in their patient. They also noted that two other cases of a primary melanoma in the thymus had been reported in the Japanese literature. Data were not presented on whether these lesions were immunoreactive to S-100 or HMB-45 antigens. Fushimi and colleagues (2000), however, presented a melanotic lesion of the thymus that was positive for HMB-45 and S-100. Other small pigmented cells were also present that contained melanin but were negative to the antigen for HMB-45, as was an associated benign, giant pigmented nevus of the skin in the patient. Alli and co-workers (2000) presented a third possible primary melanoma of the thymus, but the data were insufficient for complete acceptance of this case. A malignant, nonseminomatous germ cell tumor lacks these antigens but in microscopic appearance may be confused at times with a melanoma. Furthermore, a pigmented thymic carcinoid has been reported by Ho and Ho (1977) that might cause diagnostic confusion.
Myoid Tumors of the Thymus
Two possible myoid tumors of the thymus have been reported. The first was recorded by Henry (1972). The tumor was cystic in nature, and whorls of epithelial cells were in intimate relationship with large rounded cells that were considered to have the morphologic features of thymic striated muscle cells. Phosphotungstic and hematoxylin staining of these cells revealed the presence of numerous myofibrils. These cells had the ultrastructural features of striated muscle (myoid) cells. The author's conclusion was that the tumor was possibly a thymic blastoma. The second case was reported by Murakami and associates (1984). The lesion was composed of both epithelial and myoid cells. The latter cells occurred in clusters and showed prominent, massive proliferation between areas of epithelial cells. The histologic and electron microscopic features of the myoid cells were typical of striated muscle cells. Whether this was a true myoid cell tumor or only a variation of an epithelial thymoma was not then and never has been resolved.
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