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Prognostic Factors for Thymic Epithelial Neoplasms, with Emphasis on Tumor Staging
Hematol Oncol Clin N Am 22 (2008) 527–542
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA
Prognostic Factors for Thymic Epithelial Neoplasms, with Emphasis on Tumor Staging Mark R. Wick, MD Division of Surgical Pathology and Cytopathology, Room 3020, 1215 Lee Street, University of Virginia Medical Center, University of Virginia Health System, University of Virginia Hospital, Charlottesville, VA 22908-0214, USA
T
he process of codifying the term ‘‘thymoma’’ has had a stormy history. In the not very distant past, other lesions—including lymphomas, germ cell tumors, and various mesenchymal neoplasms—were erroneously grouped with true thymic epithelial tumors under the rubric of ‘‘thymoma’’ if they arose in the anterior mediastinum [1–3]. Moreover, any thymic neoplasm that behaved aggressively was classified by some investigators as a ‘‘thymic carcinoma,’’ often with baffling modifying adjectives (Table 1) [1,4]. The end-result of these missteps was to obfuscate the behavior of verifiable thymomas and their responses to various therapies. DEFINITIONS AND TERMINOLOGY In this article, ‘‘thymoma’’ is defined as a neoplasm comprising cells that show differentiation toward keratin-containing, p63-positive thymic epithelium, and which manifest no more than moderate cytologic atypia [5–8]. Moreover, this tumor is, by further definition, invested with intralesional lymphocytes in variable numbers, which demonstrate an immunophenotype featuring reactivity for CD99 and terminal deoxynucleotidyl transferase (TdT) [9–12]. The latter histologic and immunophenotypic profile excludes another thymic epithelial neoplasm; namely, primary thymic carcinoma (PTC), because it shows overt nuclear anaplasia, often manifests CD5-reactivity, and lacks CD99/TdT-positive lymphocytes [10,11]. That is an important point, inasmuch as the biologic behavior of PTC diverges significantly from that of thymoma. PTC is an overt and typically pernicious malignancy [13,14], whereas thymoma is a tumor of borderline (indolent) aggressivity [15]. Thus, thymoma often may behave in an untoward manner, but it does so somewhat unpredictably over a relatively long time, and usually with confinement to regional E-mail address: [email protected]
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Table 1 Lowenhaupt classification of thymic epithelial tumors Classification
Description
Group I
Carcinoma of primitive epithelial reticulum Carcinomas of variegated cell pattern Carcinoma of the granulomatous pattern (thymic Hodgkin disease) Carcinoma of thymic round cells Encapsulated (benign) thymoma Carcinoma of the adamantinomatous pattern
Group II Group III
Group IV Group V Group VI
Data from Lowenhaupt E. Tumors of the thymus in relation to the thymic epithelial anlage. Cancer 1948;1:547–63.
anatomic locations in the thorax. In the Mayo Clinic experience, only 3% of patients with bona fide thymoma experienced secondary spread to sites outside the chest (metastasizing thymoma) [6]. On the other hand, approximately 75% of thymomas manifest invasion through their fibrous capsules and direct growth into contiguous structures in the thorax; 75% of those lesions also involve the pleural surfaces or pericardium. Capsule-transgressing tumors are best called ‘‘invasive thymoma,’’ because an alternative term—‘‘malignant thymoma’’ [16]—blurs the aforementioned clinicopathologic distinction from PTC and consistently causes confusion.
INVASIVE BEHAVIOR BY THYMOMA AND ITS GENERAL RELATIONSHIP TO PROGNOSIS Because of past confusion over the cellular nature of thymic epithelial neoplasms, their relative rarity, and the diverse (and often baffling) terms applied to them, efforts at stratifying thymomas into prognostically meaningful groups were hindered for a prolonged period. Encapsulated thymomas were longcalled ‘‘benign,’’ [17] but Fechner [18] and LeGolvan and Abell [19] were among the first to show that even those lesions recurred in 10% to 15% of cases. In 1973, Bernatz and colleagues [20] demonstrated a clear survival-disadvantage for patients with patently invasive thymic epithelial tumors. In that series, the 5-year survival rate for patients with encapsulated lesions was 80%, whereas only 23% of individuals with invasive thymomas were alive at the same reference-point. This differential outcome was maintained at 10 years’ surveillance. In the succeeding 35 years, several other studies have reported essentially the same results [21–34].
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OTHER PUTATIVELY PROGNOSTIC FACTORS REGARDING THYMOMA In the 1960s and 1970s, it was believed that the concurrence of myasthenia gravis with thymoma affected prognosis adversely [17,35]. However, when institutional case-type biases were excluded, that association disappeared [6,20,36,37]. Moreover, advances in the medical management of myasthenia made thoracic surgery for thymoma increasingly more feasible and postoperative recovery less tenuous, improving overall outcome in that subgroup of patients with thymic neoplasms [6,38]. Hence, it is currently accepted that myasthenia gravis has no substantive effect on the prognosis of patients with thymoma. On the other hand, some additional paraneoplastic conditions that are linked to thymoma do affect overall outcome. In particular, acquired hypogammaglobulinemia and pure red cell aplasia are chronic hematologic disorders that cause significant morbidity in their own rights. Therefore, when they are seen in association with thymoma, the same effect pertains [39,40]. Other thymoma-related paraneoplasias that increase morbidity—and may sometimes augment mortality—include dermatomyositis-polymyositis, inflammatory bowel disease, pernicious anemia, scleroderma, rheumatoid arthritis, and amyloidosis [40,41]. Thus, all of the above-cited conditions must be considered statistically when judging the relative effect of invasion by thymoma on prognosis. The microscopic variability of thymomas is considerable, perhaps second only to that of teratomas among all mediastinal neoplasms. Furthermore, nuances in the histologic traits of thymomas are important in differential diagnosis with other lesions. These can be outlined using the classification scheme of Bernatz and colleagues [42], which divides thymomas into four discrete categories based on cross-sectional microscopic morphology: lymphocyte-predominant (greater than 66% lymphocytes), epithelial-predominant (greater than 66% epithelial cells), mixed-lymphoepithelial (34%–66% epithelial cells), and spindle-cell (a special subtype of epithelial-predominant thymoma featuring a nearly exclusive composition by fusiform cells). With the exception of spindle-cell thymomas, which typically pursue an innocuous course, the Bernatz system does not represent—and was not intended as—a prognostic classification. Rather, its usefulness is as a cue mechanism for histologic differential diagnosis. In fact, there is currently no scheme for microscopically subcategorizing thymomas that correlates perfectly with behavior [43–45], including one proposed by Marino, Muller-Hermelink, and colleagues [43,44]. That system (usually abbreviated as the MMH classification) is based on the putative resemblance of thymomatous epithelial cells to those of the normal thymic cortex (‘‘cortical’’ thymomas, usually equating to Bernatz lymphocyte-predominant, mixed lymphoepithelial, and most epithelial-predominant lesions) or medulla (‘‘medullary’’ thymomas, which are largely synonymous with spindle cell lesions in the Bernatz system) [31,32,43–47]. Medullary thymomas have a good prognosis, whereas cortical lesions (including those with
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modest cytologic atypia, termed ‘‘well-differentiated thymic carcinoma’’ by Kirchner and colleagues [48]) are said to have a relatively unfavorable evolution and ‘‘mixed cortical/medullary’’ tumors are felt to manifest an intermediary behavior. It has long been known that spindle-cell (medullary) thymomas [6,33,49] generally have an innocuous behavior. In light of that fact, the author would argue that the purported prognostic value of the MMH scheme [50–52] should be reevaluated after pure spindle-cell neoplasms have been excluded from statistical analyses. As summarized by Shimosato and Mukai [53], it seems that the MMH system is, in actuality, a derivation of the Bernatz classification scheme, but with different terminology. Moreover, problems have been reported with interobserver reproducibility of the histologic classification of thymomas [45,54], and Moran and Suster [55] have aptly summarized the considerable effects of sampling bias on that process. In 1999, Rosai [56] published the second edition of Histologic Typing of Tumors of the Thymus, under the auspices of the World Health Organization (WHO) International Histologic Classification of Tumors project. In an effort to reconcile the Bernatz and MMH schemes, a hybrid system was advanced. It categorized thymomas as: Type A (spindle cell or medullary)—composed of a population of neoplastic thymic epithelial cells having a spindle or oval shape, lacking nuclear atypia, and accompanied by few or no nonneoplastic lymphocytes. Type AB—foci having the features of type A thymoma admixed with foci rich in lymphocytes. Type B1—resembling the normal functional thymus in that it combines large expanses having an appearance practically indistinguishable from normal thymic cortex with areas resembling thymic medulla. Type B2—the neoplastic epithelial component appears as scattered plump cells with vesicular nuclei and distinct nucleoli among a heavy population of lymphocytes. Perivascular spaces are common and sometimes very prominent. A perivascular arrangement of tumor cells resulting in a palisading effect may be seen. Type B3—predominantly composed of epithelial cells having a round or polygonal shape and exhibiting no or mild atypia. They are admixed with a minor component of lymphocytes, resulting in a sheet-like growth of the neoplastic cells. This histotype is synonymous with ‘‘well-differentiated thymic carcinoma,’’ as cited previously. Type C—thymomas that are outright thymic carcinomas, with obvious cytologic anaplasia.
Since the introduction of this system, several publications have claimed that the WHO classification is prognostic [27,57–60], even though it was not intended to be [61]. The author’s conclusions regarding that assertion are similar to those expressed earlier in regard to the MMH scheme. Another proposal appeared virtually simultaneously with the WHO monograph, and was advanced by Suster and Moran. It holds that thymic epithelial
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tumors can be divided into ‘‘thymomas’’ (corresponding to WHO type A, AB, B1, and B2 tumors), ‘‘atypical thymomas’’ (WHO type B3 lesions), and ‘‘thymic carcinomas’’ (PTCs, WHO type C tumors) [62,63]. The author strongly endorses that practical paradigm.
FORMAL STAGING OF THYMOMAS As show by the foregoing comments, the author does not subscribe to the purely-histologic prognostication of thymomas and continues to believe [64] that the best method for predicting the behavior of such tumors is through attention to their macroscopic growth patterns. This tenet is not new; it was first suggested by Bernatz and colleagues [20] and formalized later by Bergh and colleagues [65], Wilkins and Castleman [66], and Masaoka and colleagues [67]. The specific elements of staging schemes presented by those investigators are shown in Table 2 Among them, the Masaoka system, as advanced in 1981, has been used the most widely and tested the most extensively in clinical practice. It fundamentally separates those thymomas that are encapsulated from others that grow through the tumor capsule into surrounding soft tissue, from still other tumors that involve additional viscera. In the last of those categories, a stage-specific distinction, is made between lesions that infiltrate other organs by direct extension as opposed to true metastasis. Table 2 Comparison of Masaoka, Bergh, and Wilkins-Castleman staging systems for thymoma Masaoka system [67]
Bergh system [65]
Wilkins-Castleman system [66]
Stage I—Macroscopically and microscopically completely encapsulated Stage II—Macroscopic invasion into surrounding fatty tissue or mediastinal pleura (stage IIb) or microscopic invasion into the capsule (stage IIa) Stage III—Macroscopic invasion into adjacent organs or intrathoracic metastases Stage IVa—Pleural or pericardial implants or dissemination Stage IVb—Nodal or hematogenous metastases
Stage I—Intact capsule or tumor growth within the capsule Stage II—Pericapsular tumor growth into mediastinal fat
Stage 1—Intact capsule or tumor growth within the capsule Stage II—Pericapsular tumor growth into mediastinal fat, adjacent pleura, or pericardium
Stage III—Invasive tumor growth into surrounding organs or intrathoracic metastasis
Stage III—Invasive tumor growth into surrounding organs or intrathoracic metastasis
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In the original publication by Masaoka and colleagues [67], several conclusions were made in a thorough study of 96 thymomas that had been treated at one institution in Japan. Those conclusions are the following: Complete excision of thymoma was the single most optimal therapeutic measure, even if it required en bloc removal of a significant portion of the perithymic soft tissue or an adjacent organ, such as the lung; Radiotherapy for invasive tumors appeared to hinder their local recurrence; A statistically significant difference could be demonstrated in the survival of patients with stage I (gland-confined) tumors, as compared with others who had stage III or stage IV thymomas (involving regional structures) (Fig. 1); and Stage IVb (metastasizing) tumors were rare, comprising only 3% of all thymomas.
In the intervening 26 years, the validity of these statements has been affirmed and they have been used to structure predefined therapeutic approaches for thymoma. For example, chemotherapy—sometimes with irradiation as well—is currently given routinely to patients with stage III or stage IV thymomas (Figs. 2 and 3), usually in a neoadjuvant setting [34,68–70]. The management of stage II lesions (Fig. 4) is more controversial at present. Although some studies continue to advocate the use of irradiation for that group [71], the latter treatment is inconsistently used and may not be necessary [72–75]. The author’s own meta-analysis of the literature on stage II thymomas indicates that their overall prognosis is not significantly different from that of stage I tumors (Fig. 5), with or without radiotherapy [76]. Two other controversial points that are tied to stage-based therapy relate to unequivocally aggressive thymic epithelial tumors. Stage IVa lesions—which involve the pleural surfaces, or pericardium, or both—have been managed in some small series with pleuropneumonectomy and pericardiectomy. Some investigators have advocated this approach, together with preoperative and postoperative chemotherapy [77], whereas others have denigrated it as ineffective
Fig. 1. Survival curve for thymomas studied in the original series by Masaoka and colleagues, as divided into four strata. (Data from Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48:2485–92.)
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Fig. 2. Histologic image of Masaoka stage III thymoma, demonstrating tumor (upper left) directly invading lung parenchyma (hematoxylin and eosin stain 200).
or even harmful [78]. In similar counterpoint, Masaoka staging has been variously supported [29,79] or opposed [80] as a prognostic tool for PTCs. The Groupe d’Etudes Des Tumeurs Thymiques Modification of the Masaoka Staging System for Thymoma In the late 1980s, the Groupe d’Etudes des Tumeurs Thymiques (GETT; French Study Group on Thymic Tumors) initiated the construction of a derivative Masaoka staging system that was principally tied to surgical therapy for thymomas (Table 3) [81,82]. The resulting GETT scheme has been tested clinically in the interim and found to perform well in a predictive fashion [36]. Tumor-Nodal-Metastasis Staging of Thymoma and Thymic Carcinoma In an attempt to conform with the staging systems for various malignancies that have been advanced by the American Joint Committee on Cancer, Yamakawa and colleagues [83] also suggested using a TNM (tumor substage-nodal statusmetastasis) scheme for the staging of thymoma. That proposal was followed
Fig. 3. Two Masaoka stage IV thymomas. (A) This Masaoka stage IVa thymoma shows obvious growth around the great mediastinal blood vessels and involvement of the right pleura in a computed tomogram. (B) Another case of thymoma demonstrates multifocal embolic metastasis to the lung parenchyma in a computed tomogram, establishing a Masaoka stage of IVb.
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Fig. 4. Masaoka staged thymomas. (A) This computed tomogram demonstrates a thymic mass with only questionable involvement of the adjacent mediastinal soft tissue. (B) An ‘‘extended’’ thymectomy specimen is shown here, demonstrating invasion of a thymoma into the mediastinal fat (Masaoka stage IIb). The final surgical margins were uninvolved. (C) This thymoma shows microscopic invasion into, but not through, the fibrous tumor capsule (Masaoka stage IIa) (hematoxylin and eosin stain 200). (D) A mushroom-shaped protrusion of tumor is seen breaching the fibrous tumor capsule in this Masaoka stage IIb thymoma (hematoxylin and eosin stain 150).
several years later by a similar TNM paradigm for PTC, as advanced by Tsuchiya and colleagues (Table 4) [84]. These propositions are problematic because their publication did not follow prospective trials to see whether their composite elements performed adequately in the clinical context of comparable treatment modalities. Moreover, to the best of the author’s awareness, the TNM substrata were created intuitively rather than being tied to a rigorous statistical modeling procedure. Thus, from the perspective of evidence-based medicine, one must be skeptical of their soundness unless and until the TNM systems for thymic tumors are tested systematically. Other Iterations of the Masaoka Staging System One of the most interesting permutations of the classic Masaoka scheme is that reported by Asamura and colleagues [85]. Those investigators constructed two testable staging systems in reference to patients with thymomas of different stages who had been treated at a single institution. Classic Masaoka stage I was combined with stage II to yield stage IA (for Asamura) in both proposed staging
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Fig. 5. Masaoka stage I thymoma. (A) An anterior mediastinal mass is present in this chest radiograph, projecting into the right hemithorax. Excision of the lesion demonstrated an encapsulated tumor with internal fibrous septa (B), representing a Masaoka stage I thymoma. (C) Microscopic examination of the lesion confirmed its containment by the fibrous capsule (hematoxylin and eosin stain 200); (D) it manifested histologic heterogeneity from region to region, but was generally epithelial-predominant (hematoxylin and eosin stain 400).
Table 3 Groupe d’Etudes des Tumeurs Thymiques staging system for thymoma Classification
Description
Stage IA Stage IB
Encapsulated, completely resected Macroscopically completely resected but suspicion of mediastinal adhesions or potential capsular invasion at surgery Invasive tumor, completely resected Invasive tumor, subtotal resection Invasive tumor, biopsy alone Supraclavicular or pleural metastasis Distant metastases
Stage Stage Stage Stage
II IIIA IIIB IVA
Stage IVB
Data from Gamondes JP, Balawi A, Greenland T, et al. Seventeen years of surgical treatment of thymoma: factors influencing survival. Eur J Cardiothorac Surg 1991;5:124–131.
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Table 4 Proposed TNM schemes for thymoma and thymic carcinoma Thymoma pT Substage pT1 pT2
Description Completely encapsulated tumor Tumor breaking through capsule, invading thymus or fatty tissue Tumor breaking through the mediastinal pleura or pericardium, or invading neighboring organs, such as great vessels and lung Tumor with pleural or pericardial implantation
pT3
pT4 pN Substage pN0 pN1 pN2
No lymph node metastasis Metastasis in anterior mediastinal lymph nodes Metastasis in intrathoracic lymph nodes excluding anterior mediastinal lymph nodes Metastasis in extrathoracic lymph nodes
pN3 pM Substage pM0 pM1 Thymic carcinoma pT Substage pT1 pT2
No distant organ metastasis With distant metastasis
Completely encapsulated tumor Tumor breaking through capsule, invading thymus or fatty tissue Tumor breaking through the mediastinal pleura or pericardium, or invading neighboring organs, such as great vessels and lung Tumor with pleural or pericardial implantation
pT3
pT4 pN Substage pN0 pN1
No lymph node metastasi Metastasis in anterior mediastinal lymph nodes Metastasis in intrathoracic lymph nodes excluding anterior mediastinal lymph nodes Metastasis in extrathoracic lymph nodes
pN2 pN3 pM Substage pM0 pM1 Primary tumor Stage I Stage II Stage III Stage IVa Stage IVb Stage IVc
No distant organ metastasis With distant metastasis T1, T2 T1, T2 T3 T4 any T any T
Lymph node status N0 N1 N0, N1 N0, N1 N2, N3
Distant metastasis M0 M0 M0 M0 M0
Data from Yamakawa Y, Masaoka A, Hashimoto T, et al. A tentative tumor-node-metastasis classification of thymoma. Cancer 1991;68:1984–7; and Tsuchiya R, Koga K, Matsuno Y, et al. Thymic carcinoma: proposal for pathological TNM staging. Pathol Int 1994;44:505–12.
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schemes. Stages II and III tumors were defined as invasive thymomas, with varying combinations of tumor diameter, and involved adjacent structures, as represented in the two proposed systems. In the first of these, ‘‘Scheme 1’’, stage IIA lesions were defined as masses up to 10 cm in maximal dimension and involving no more than one regional structure or organ. Stage IIIA neoplasms were represented by lesions of all sizes that involved more than two regional structures or organs. In ‘‘Scheme 2,’’ stage II thymomas were lesions of all sizes that involved only one regional structure or organ, and stage III tumors were greater than 10 cm in maximal size as well as involving more than two adjacent structures or organs. Comparisons of case outcome were done according to the classic Masaoka staging system, and Schemes 1 and 2 of Asamura and colleagues. Survival curves for Asamura Scheme 1 yielded the most balanced distribution of patients in each staging group. These data further support the merging of classic Masaoka stages I and II, and they indicate that tumor size and a codified extent of regional growth add further discrimination to staging. CURRENT METHODOLOGIC PROBLEMS IN STAGING THYMIC NEOPLASMS Definitive treatment for thymic epithelial tumors has been predicated in an attempt at their complete surgical removal; in most medical centers, that statement still pertains [86–89]. Surgical exploration and resection allows for direct visualization of tumor growth by the surgeon and the pathologist, and many publications have attested to the survival-advantage of excising all grossly-visible disease [28,70–72]. Admittedly, problems may arise in distinguishing true invasion from fibrous adhesions between thymomas and adjacent structures. However, the author believes that it is much better to visually inspect the areas in question and biopsy them when possible, than it is to rely on imaging studies to define invasive growth. Hence, formal therapeutic thoracotomy, or alternatively, thoracoscopy and multifocal excisional biopsies, should be the initial steps in the clinical staging
Fig. 6. This fine needle aspiration biopsy of a thymic mass shows large loosely cohesive epithelioid cells admixed with lymphocytes, consistent with the cytologic image of thymoma. That impression was confirmed by positive immunostaining for pankeratin, p63, and CD99. (Papanicolaou stain 400).
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of thymic epithelial lesions. That is true even for those thymomas that are felt to be stage III or stage IV neoplasms at presentation. Over the past 15 years, an increasing trend has appeared toward establishing a pathologic diagnosis of thymoma using very small tissue samples (eg, by fineneedle aspiration biopsy shown in Fig. 6 [90] or cutting-needle-core biopsy) and immunohistology or electron microscopy [91]. Thereafter, the results of imaging studies are often used to stage the tumor and guide nonsurgical therapy. This approach is generally acceptable, but it does have several distinct drawbacks. First, cases are encountered in which pleural or pulmonary lesions are felt to represent high-stage metastatic disease radiographically, but are subsequently shown to be nonneoplastic or nonthymic after eventual tissue sampling is done. In those circumstances, the risk of morbid over-treatment is a real one. Secondly, the radiographic separation of stage I from stage II thymomas is imprecise [34], even with high-resolution computed tomography or magnetic resonance imaging [92–94]. Admittedly, that problem may well be moot in light of the comparable biologic behavior of those two tumor groups. Finally, Suster and Moran [63,95] have shown that some thymomas undergo clonal evolution to yield areas of PTC in the same mass. The latter foci may easily be missed in small biopsy samples [55]. Thus, clinicians caring for patients with thymic neoplasms must recognize that nonpathologic staging procedures may be associated with problematic responses to treatment or an unexpected clinical evolution. In that eventuality, tissue procurement from indeterminate clinical or radiographic lesions is advisable to clarify the situation. The staging of de novo PTCs is problematic under any circumstance. Along with Blumberg and colleagues [80], the author believes that neither the GETT nor the Masaoka systems reliably predict the evolution of such tumors. For example, the author has seen several completely encapsulated PTCs that metastasized widely. Until another tenable paradigm for prognosticating such tumors is compiled, one must assume that most thymic carcinomas have a definite potential for both local recurrence and distant metastasis [13,14,96–100] and treat patients accordingly. The only exceptions to that statement concern rare lowgrade PTCs, such as basaloid carcinoma, mucoepidermoid carcinoma, and well-differentiated encapsulated squamous-cell carcinoma [14,101]. References [1] Binkley FM, Thorburn JD, Stephens HB, et al. Mediastinal tumors of thymic origin. Calif Med 1953;78:267–73. [2] Soutter L, Sommers S, Relman AS, et al. Problems in the surgical management of thymic tumors. Ann Surg 1957;146:424–37. [3] Sellors TH, Thackray AC, Thomson AD. Tumors of the thymus. Thorax 1967;22:193–221. [4] Lowenhaupt E. Tumors of the thymus in relation to the thymic epithelial anlage. Cancer 1948;1:547–63. [5] Rosai J, Levine GD. Thymic hyperplasia and neoplasia: a review of current concepts. Hum Pathol 1978;9:495–515. [6] Lewis JE, Wick MR, Scheithauer BW, et al. Thymomas: a clinicopathologic review. Cancer 1987;60:2727–43.
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[7] Dotto J, Pelosi G, Rosai J. Expression of p63 in thymomas and normal thymus. Am J Clin Pathol 2007;127:415–20. [8] Pan CC, Chen PC, Chou TY, et al. Expression of calretinin and other mesothelioma-related markers in thymic carcinomas and thymoma. Hum Pathol 2003;34:1155–62. [9] Chan JKC, Tsang WY, Sereviratne S, et al. The MIC2 antibody 013: practical application for the study of thymic epithelial tumors. Am J Surg Pathol 1995;19:1115–23. [10] Kuo TT, Chan JKC. Thymic carcinoma arising in thymoma is associated with alterations in immunohistochemical profile. Am J Surg Pathol 1998;22:1474–81. [11] Dorfman DM, Shahsafaei A, Chan JKC. Thymic carcinomas, but not thymomas and carcinomas of other sites, show CD5-immunoreactivity. Am J Surg Pathol 1997;21:936–40. [12] Woda BA, Bain K, Vander Salm T. The phenotype of lymphocytes in thymoma as studied with monoclonal antibodies. Clin Immunol Immunopathol 1984;30:197–201. [13] Ritter JH, Wick MR. Primary carcinomas of the thymus gland. Semin Diagn Pathol 1999;16:18–31. [14] Suster S, Moran CA. Thymic carcinoma: spectrum of differentiation and histologic types. Pathology 1998;30:111–22. [15] Riedel RF, Burfeind WR Jr. Thymoma: benign appearance, malignant potential. Oncologist 2006;11:887–94. [16] Lara PN Jr. Malignant thymoma: current status and future directions. Cancer Treat Rev 2000;26:127–31. [17] Wilkins EW, Edmunds LH Jr, Castleman B. Cases of thymoma at the Massachusetts General Hospital. J Thorac Cardiovasc Surg 1966;52:322–30. [18] Fechner RE. Recurrence of noninvasive thymomas: report of four cases and review of literature. Cancer 1969;23:1423–7. [19] LeGolvan DP, Abell MR. Thymomas. Cancer 1977;39:2142–57. [20] Bernatz PE, Khonsari S, Harrison EG Jr, et al. Thymoma: factors influencing prognosis. Surg Clin North Am 1973;53:885–92. [21] Cowen D, Hannoun-Levi J-M, Rosbeut M, et al. Natural history and treatment of malignant thymoma. Oncology 1998;12:1001–5. [22] Pollack A, Komaki R, Cox JD, et al. Thymoma: treatment and prognosis. Int J Radiat Oncol Biol Phys 1992;23:1037–43. [23] Verley JM, Hollmann KH. Thymoma: a comparative study of clinical stages, histologic features, and survival in 200 cases. Cancer 1985;55:1074–86. [24] Monden Y, Nakahara K, Iioka S, et al. Recurrence of thymoma: clinicopathological features, therapy, and prognosis. Ann Thorac Surg 1985;39:165–9. [25] Maggi G, Giaccone G, Donadio M, et al. Thymomas: a review of 169 cases with particular reference to results of surgical treatment. Cancer 1986;58:765–76. [26] Ribet C, Voisin C, Gosselin B, et al. Les thymomes lympho-epitheliaux: Etude anatomo-clinique et therapeutique de 113 cas. Rev Mal Respir 1988;5:53–60. [27] Park MS, Chung KY, Kim KD, et al. Prognosis of thymic epithelial tumors according to the new World Health Organization histologic classification. Ann Thorac Surg 2004;78:992–8. [28] Rea F, Marulli G, Girardi R, et al. Long-term survival and prognostic factors in thymic epithelial tumors. Eur J Cardiothorac Surg 2004;26:412–8. [29] Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 2003;76:878–84. [30] Nakagawa K, Asamura H, Matsuno Y, et al. Thymoma: a clinicopathologic study based on the new World Health Organization classification. J Thorac Cardiovasc Surg 2003;126: 1134–40. [31] Rios A, Torres J, Galindo PJ, et al. Prognostic factors in thymic epithelial neoplasms. Eur J Cardiothorac Surg 2002;21:307–13. [32] Lardinois D, Rechsteiner R, Lang RH, et al. Prognostic relevance of Masaoka and MullerHermelink classification in patients with thymic tumors. Ann Thorac Surg 2000;69: 1550–5.
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[33] Gripp S, Hilgers K, Wurm R, et al. Thymoma: prognostic factors and treatment outcomes. Cancer 1998;83:1495–503. [34] Kesler KA, Wright CD, Loehrer PJ Sr. Thymoma: current medical and surgical management. Semin Neurol 2004;24:63–73. [35] Salyer WR, Eggleston JC. Thymoma: a clinical and pathological study of 65 cases. Cancer 1976;37:229–49. [36] Regnard JF, Magdeleinat P, Dromer C, et al. Prognostic factors and long-term results after thymoma resection: a series of 307 patients. J Thorac Cardiovasc Surg 1996;112: 376–81. [37] Wilkins EW Jr, Grillo HC, Scannell JG, et al. Role of staging in prognosis and management of thymoma. Ann Thorac Surg 1991;51:888–92. [38] de Perrot M, Liu J, Bril V, et al. Prognostic significance of thymomas in patients with myasthenia gravis. Ann Thorac Surg 2002;74:1658–62. [39] Sonobe M, Nakagawa M, Ichinose M, et al. Thymoma: analysis of prognostic factors. Jpn J Thorac Cardiovasc Surg 2001;49:35–41. [40] Morgenthaler TI, Brown LR, Colby TV, et al. Thymoma. Mayo Clin Proc 1993;68: 1110–23. [41] Souadjian JV, Enriquez P, Silverstein MN, et al. The spectrum of diseases associated with thymoma: coincidence or syndrome? Arch Intern Med 1974;134:374–9. [42] Bernatz PE, Harrison EG Jr, Clagett OT. Thymoma: a clinicopathologic study. J Thorac Cardiovasc Surg 1961;42:424–44. [43] Marino M, Muller-Hermelink HK. Thymoma and thymic carcinoma: relation of thymoma epithelial cells to the cortical and medullary differentiation of thymus. Virchows Arch A Pathol Anat Histopathol 1985;407:119–49. [44] Muller-Hermelink HK, Marino M, Palestro G. Pathology of thymic epithelial tumors. Curr Top Pathol 1986;75:207–68. [45] Kornstein MJ. Controversies regarding the pathology of thymomas. Pathol Annu 1992;27(Part 2):1–15. [46] Pescarmona E, Rendina EA, Venuta F, et al. Analysis of prognostic factors and clinicopathological staging of thymoma. Ann Thorac Surg 1990;50:534–8. [47] Lequaglie C, Giudice G, Brega-Massone PP, et al. Clinical and pathologic predictors of survival in patients with thymic tumors. J Cardiovasc Surg 2002;43:269–74. [48] Kirchner T, Schalke B, Buchwald J, et al. Well-differentiated thymic carcinoma: an organotypical low-grade carcinoma with relationship to cortical thymoma. Am J Surg Pathol 1992;16:1153–69. [49] Pan CC, Chen WY, Chiang H. Spindle-cell and mixed spindle-cell/lymphocytic thymomas: an integrated clinicopathologic and immunohistochemical study of 81 cases. Am J Surg Pathol 2001;25:111–20. [50] Kuo TT, Lo SK. Thymoma: a study of the pathologic classification of 71 cases with evaluation of the Muller-Hermelink system. Hum Pathol 1993;24:766–71. [51] Pescarmona E, Rendina EA, Venuta F, et al. The prognostic implication of thymoma histologic subtyping: a study of 80 consecutive cases. Am J Clin Pathol 1990;93:190–5. [52] Quintanilla-Martinez L, Wilkins EW Jr, Ferry JA, et al. Thymoma—morphologic subclassification correlates with invasiveness and immunohistologic features: a study of 122 cases. Hum Pathol 1993;24:958–69. [53] Shimosata Y, Mukai K. Tumors of the mediastinum. In: Rosai J, editor. Atlas of tumor pathology, Series 3. Fascicle 21. Washington, DC: Armed Forces Institute of Pathology; 1997. p. 33–273. [54] Dawson A, Ibrahim NB, Gibbs AR. Observer variation in the histopathological classification of thymomas: correlation with prognosis. J Clin Pathol 1994;47:519–23. [55] Moran CA, Suster S. On the histologic heterogeneity of thymic epithelial neoplasms: impact of sampling in subtyping and classification of thymomas. Am J Clin Pathol 2000;114:760–6.
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[56] Rosai J. Histological typing of tumors of the thymus by the World Health Organization. 2nd edition. Berlin: Springer-Verlag; 1999. p. 9–15. [57] Chen G, Marx A, Wen-Hu C, et al. New WHO classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 2002;95:420–9. [58] Okumura M, Ohta M, Miyoshi S, et al. Oncological significance of WHO histological thymoma classification: a clinical study based on 286 patients. Jpn J Thorac Cardiovasc Surg 2002;50:189–94. [59] Okumura M, Ohta M, Tateyama H, et al. The World Health Organization histologic classification System reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer 2002;94:624–32. [60] Okumura M, Miyoshi S, Fujii Y, et al. Clinical and functional significance of WHO classification on human thymic epithelial neoplasms: a study of 146 consecutive tumors. Am J Surg Pathol 2001;25:103–10. [61] Dadmanesh F, Sekihara T, Rosai J. Histologic typing of thymoma according to the new World Health Organization classification. Chest Surg Clin N Am 2001;11: 407–20. [62] Suster S, Moran CA. Thymoma, atypical thymoma, and thymic carcinoma: a novel conceptual approach to the classification of thymic epithelial neoplasms. Am J Clin Pathol 1999;111:826–33. [63] Suster S, Moran CA. Primary thymic epithelial neoplasms: spectrum of differentiation and histological features. Semin Diagn Pathol 1999;16:2–17. [64] Wick MR. Assessing the prognosis of thymomas. Ann Thorac Surg 1990;50:521–2. [65] Bergh NP, Gatzinsky P, Larsson S, et al. Tumors of the thymus and thymic region. I. Clinicopathological studies on thymomas. Ann Thorac Surg 1978;25:91–8. [66] Wilkins EW, Castleman B. Thymoma: a continuing survey at the Massachusetts General Hospital. Ann Thorac Surg 1979;28:252–6. [67] Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48:2485–92. [68] Stremmel C, Dango S, Thiemann U, et al. [Thymoma—incidence, classification, and therapy]. Dtsch Med Wochenschr 2007;132:2090–5 [in German]. [69] Shin DM, Walsh GL, Komake R, et al. A multidisciplinary approach to therapy for unresectable malignant thymoma. Ann Intern Med 1998;129:100–4. [70] Blumberg D, Port JL, Weksler B, et al. Thymoma: a multivariate analysis of factors predicting survival. Ann Thorac Surg 1995;60:908–13. [71] Mehran R, Ghosh R, Maziak D, et al. Surgical treatment of thymoma. Can J Surg 2002;45: 25–30. [72] Singhal S, Shrager JB, Rosenthal DI, et al. Comparison of stages I and II thymoma treated by complete resection with or without adjuvant radiation. Ann Thorac Surg 2003;76: 1635–42. [73] Rena O, Papalia E, Oliaro A, et al. Does adjuvant radiation therapy improve disease-free survival in completely resected Masaoka stage II thymoma? Eur J Cardiothorac Surg 2007;31:109–13. [74] Mangi AA, Wright CD, Allan JS, et al. Adjuvant radiation therapy for stage II thymoma. Ann Thorac Surg 2002;74:1033–7. [75] Ogawa K, Uno T, Toita T, et al. Postoperative radiotherapy for patients with completely-resected thymoma: a multi-institutional, retrospective review of 103 patients. Cancer 2002;94:1405–13. [76] Marchevsky AM, Gupta R, McKenna RJ, et al. Evidence-based pathology and the pathologic evaluation of thymomas: there is no difference in disease-free and overall survival in patients with stages I and II thymoma. Arch Pathol Lab Med; 2008, in press. [77] Wright CD. Pleuropneumonectomy for the treatment of Masaoka stage IVa thymoma. Ann Thorac Surg 2006;82:1234–9.
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[78] Haniuda M, Kondo R, Numanami H, et al. Recurrence of thymoma: clinicopathological features, reoperation, and outcome. J Surg Oncol 2001;78:183–8. [79] Luebke T, Beckurts KT, Wickenhauser C, et al. Masaoka staging is of prognostic relevance in type B3/C thymomas. Anticancer Res 2004;24:4113–9. [80] Blumberg D, Burt ME, Bains MS, et al. Thymic carcinoma: current staging does not predict prognosis. J Thorac Cardiovasc Surg 1998;115:303–8. [81] Gamondes JP, Balawi A, Greenland T, et al. Seventeen years of surgical treatment of thymoma: factors influencing survival. Eur J Cardiothorac Surg 1991;5:124–31. [82] Cowen D, Richaud P, Mornex F, et al. Thymoma: results of a multicentric retrospective series of 149 non-metastatic irradiated patients and review of the literature. FNCLCC trialists, Federation Nationale des Centres de Lutte Contre le Cancer. Radiother Oncol 1995;34:9–16. [83] Yamakawa Y, Masaoka A, Hashimoto T, et al. A tentative tumor-node-metastasis classification of thymoma. Cancer 1991;68:1984–7. [84] Tsuchiya R, Koga K, Matsuno Y, et al. Thymic carcinoma: proposal for pathological TNM staging. Pathol Int 1994;44:505–12. [85] Asamura H, Nakagawa K, Matsuno Y, et al. Thymoma needs a new staging system. Interact Cardiovasc Thorac Surg 2004;3:163–7. [86] Stremmel C, Passlick B. [Surgery of mediastinal tumors]. Chirurg 2008;79:9–17 [in German]. [87] Wright CD, Kessler KA. Surgical treatment of thymic tumors. Semin Thorac Cardiovasc Surg 2005;17:20–6. [88] Lin CS, Kuo TT, Hsu WH, et al. Management of locally-advanced unresectable thymic epithelial tumors. J Chin Med Assoc 2004;67:172–8. [89] Sugiura H, Morikawa T, Ito K, et al. Long-term results of surgical treatment for invasive thymoma. Anticancer Res 1999;19:1433–7. [90] Wakely PE. Cytopathology-histopathology of the mediastinum: epithelial, lymphoproliferative, and germ-cell neoplasms. Ann Diagn Pathol 2002;6:30–43. [91] Wick MR, Powers CN. The thymus and mediastinum. In: Silverberg SG, editor. Silverberg’s principles & practice of surgical pathology & cytopathology. 4th edition. New York: Churchill-Livingstone-Elsevier; 2006. p. 1091–134. [92] Jeong YJ, Lee KS, Kim J, et al. Does CT of thymic epithelial tumors enable us to differentiate histologic subtypes and predict prognosis? Am J Roentgenol 2004;183:283–9. [93] Sadohara J, Fujimoto K, Muller NL, et al. Thymic epithelial tumors: comparison of CT and MR imaging findings of low-risk thymomas, high-risk thymomas, and thymic carcinomas. Eur J Radiol 2006;60:70–9. [94] Inaoka T, Takahashi K, Mineta M, et al. Thymic hyperplasia and thymus gland tumors: differentiation with chemical-shift MR imaging. Radiology 2007;243:869–76. [95] Suster S, Moran CA. Primary thymic epithelial neoplasms showing combined features of thymoma and thymic carcinoma: a clinicopathologic study of 22 cases. Am J Surg Pathol 1996;20:1469–80. [96] Maruyama R, Suemitsu R, Okamoto T, et al. Persistent and aggressive treatment for thymic carcinomas: results of a single-institute experience with 25 patients. Oncology 2006;70: 325–9. [97] Lin JT, Wei-Shu W, Yen CC, et al. Stage IV thymic carcinoma: a study of 20 patients. Am J Med Sci 2005;330:172–5. [98] Kurup A, Loehrer PJ Sr. Thymoma and thymic carcinoma: therapeutic approaches. Clin Lung Cancer 2004;6:28–32. [99] Takeda S, Sawabata N, Inoue M, et al. Thymic carcinoma: clinical institutional experience with 15 patients. Eur J Cardiothorac Surg 2004;26:401–6. [100] Eng TY, Fuller CD, Jagirdar J, et al. Thymic carcinoma: state of the art review. Int J Radiat Oncol Biol Phys 2004;59:654–64. [101] Suster S, Rosai J. Thymic carcinoma: a clinicopathologic study of 60 cases. Cancer 1991;15:1025–32.
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA
Prognostic Factors for Thymic Epithelial Neoplasms, with Emphasis on Tumor Staging Mark R. Wick, MD Division of Surgical Pathology and Cytopathology, Room 3020, 1215 Lee Street, University of Virginia Medical Center, University of Virginia Health System, University of Virginia Hospital, Charlottesville, VA 22908-0214, USA
T
he process of codifying the term ‘‘thymoma’’ has had a stormy history. In the not very distant past, other lesions—including lymphomas, germ cell tumors, and various mesenchymal neoplasms—were erroneously grouped with true thymic epithelial tumors under the rubric of ‘‘thymoma’’ if they arose in the anterior mediastinum [1–3]. Moreover, any thymic neoplasm that behaved aggressively was classified by some investigators as a ‘‘thymic carcinoma,’’ often with baffling modifying adjectives (Table 1) [1,4]. The end-result of these missteps was to obfuscate the behavior of verifiable thymomas and their responses to various therapies. DEFINITIONS AND TERMINOLOGY In this article, ‘‘thymoma’’ is defined as a neoplasm comprising cells that show differentiation toward keratin-containing, p63-positive thymic epithelium, and which manifest no more than moderate cytologic atypia [5–8]. Moreover, this tumor is, by further definition, invested with intralesional lymphocytes in variable numbers, which demonstrate an immunophenotype featuring reactivity for CD99 and terminal deoxynucleotidyl transferase (TdT) [9–12]. The latter histologic and immunophenotypic profile excludes another thymic epithelial neoplasm; namely, primary thymic carcinoma (PTC), because it shows overt nuclear anaplasia, often manifests CD5-reactivity, and lacks CD99/TdT-positive lymphocytes [10,11]. That is an important point, inasmuch as the biologic behavior of PTC diverges significantly from that of thymoma. PTC is an overt and typically pernicious malignancy [13,14], whereas thymoma is a tumor of borderline (indolent) aggressivity [15]. Thus, thymoma often may behave in an untoward manner, but it does so somewhat unpredictably over a relatively long time, and usually with confinement to regional E-mail address: [email protected]
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Table 1 Lowenhaupt classification of thymic epithelial tumors Classification
Description
Group I
Carcinoma of primitive epithelial reticulum Carcinomas of variegated cell pattern Carcinoma of the granulomatous pattern (thymic Hodgkin disease) Carcinoma of thymic round cells Encapsulated (benign) thymoma Carcinoma of the adamantinomatous pattern
Group II Group III
Group IV Group V Group VI
Data from Lowenhaupt E. Tumors of the thymus in relation to the thymic epithelial anlage. Cancer 1948;1:547–63.
anatomic locations in the thorax. In the Mayo Clinic experience, only 3% of patients with bona fide thymoma experienced secondary spread to sites outside the chest (metastasizing thymoma) [6]. On the other hand, approximately 75% of thymomas manifest invasion through their fibrous capsules and direct growth into contiguous structures in the thorax; 75% of those lesions also involve the pleural surfaces or pericardium. Capsule-transgressing tumors are best called ‘‘invasive thymoma,’’ because an alternative term—‘‘malignant thymoma’’ [16]—blurs the aforementioned clinicopathologic distinction from PTC and consistently causes confusion.
INVASIVE BEHAVIOR BY THYMOMA AND ITS GENERAL RELATIONSHIP TO PROGNOSIS Because of past confusion over the cellular nature of thymic epithelial neoplasms, their relative rarity, and the diverse (and often baffling) terms applied to them, efforts at stratifying thymomas into prognostically meaningful groups were hindered for a prolonged period. Encapsulated thymomas were longcalled ‘‘benign,’’ [17] but Fechner [18] and LeGolvan and Abell [19] were among the first to show that even those lesions recurred in 10% to 15% of cases. In 1973, Bernatz and colleagues [20] demonstrated a clear survival-disadvantage for patients with patently invasive thymic epithelial tumors. In that series, the 5-year survival rate for patients with encapsulated lesions was 80%, whereas only 23% of individuals with invasive thymomas were alive at the same reference-point. This differential outcome was maintained at 10 years’ surveillance. In the succeeding 35 years, several other studies have reported essentially the same results [21–34].
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OTHER PUTATIVELY PROGNOSTIC FACTORS REGARDING THYMOMA In the 1960s and 1970s, it was believed that the concurrence of myasthenia gravis with thymoma affected prognosis adversely [17,35]. However, when institutional case-type biases were excluded, that association disappeared [6,20,36,37]. Moreover, advances in the medical management of myasthenia made thoracic surgery for thymoma increasingly more feasible and postoperative recovery less tenuous, improving overall outcome in that subgroup of patients with thymic neoplasms [6,38]. Hence, it is currently accepted that myasthenia gravis has no substantive effect on the prognosis of patients with thymoma. On the other hand, some additional paraneoplastic conditions that are linked to thymoma do affect overall outcome. In particular, acquired hypogammaglobulinemia and pure red cell aplasia are chronic hematologic disorders that cause significant morbidity in their own rights. Therefore, when they are seen in association with thymoma, the same effect pertains [39,40]. Other thymoma-related paraneoplasias that increase morbidity—and may sometimes augment mortality—include dermatomyositis-polymyositis, inflammatory bowel disease, pernicious anemia, scleroderma, rheumatoid arthritis, and amyloidosis [40,41]. Thus, all of the above-cited conditions must be considered statistically when judging the relative effect of invasion by thymoma on prognosis. The microscopic variability of thymomas is considerable, perhaps second only to that of teratomas among all mediastinal neoplasms. Furthermore, nuances in the histologic traits of thymomas are important in differential diagnosis with other lesions. These can be outlined using the classification scheme of Bernatz and colleagues [42], which divides thymomas into four discrete categories based on cross-sectional microscopic morphology: lymphocyte-predominant (greater than 66% lymphocytes), epithelial-predominant (greater than 66% epithelial cells), mixed-lymphoepithelial (34%–66% epithelial cells), and spindle-cell (a special subtype of epithelial-predominant thymoma featuring a nearly exclusive composition by fusiform cells). With the exception of spindle-cell thymomas, which typically pursue an innocuous course, the Bernatz system does not represent—and was not intended as—a prognostic classification. Rather, its usefulness is as a cue mechanism for histologic differential diagnosis. In fact, there is currently no scheme for microscopically subcategorizing thymomas that correlates perfectly with behavior [43–45], including one proposed by Marino, Muller-Hermelink, and colleagues [43,44]. That system (usually abbreviated as the MMH classification) is based on the putative resemblance of thymomatous epithelial cells to those of the normal thymic cortex (‘‘cortical’’ thymomas, usually equating to Bernatz lymphocyte-predominant, mixed lymphoepithelial, and most epithelial-predominant lesions) or medulla (‘‘medullary’’ thymomas, which are largely synonymous with spindle cell lesions in the Bernatz system) [31,32,43–47]. Medullary thymomas have a good prognosis, whereas cortical lesions (including those with
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modest cytologic atypia, termed ‘‘well-differentiated thymic carcinoma’’ by Kirchner and colleagues [48]) are said to have a relatively unfavorable evolution and ‘‘mixed cortical/medullary’’ tumors are felt to manifest an intermediary behavior. It has long been known that spindle-cell (medullary) thymomas [6,33,49] generally have an innocuous behavior. In light of that fact, the author would argue that the purported prognostic value of the MMH scheme [50–52] should be reevaluated after pure spindle-cell neoplasms have been excluded from statistical analyses. As summarized by Shimosato and Mukai [53], it seems that the MMH system is, in actuality, a derivation of the Bernatz classification scheme, but with different terminology. Moreover, problems have been reported with interobserver reproducibility of the histologic classification of thymomas [45,54], and Moran and Suster [55] have aptly summarized the considerable effects of sampling bias on that process. In 1999, Rosai [56] published the second edition of Histologic Typing of Tumors of the Thymus, under the auspices of the World Health Organization (WHO) International Histologic Classification of Tumors project. In an effort to reconcile the Bernatz and MMH schemes, a hybrid system was advanced. It categorized thymomas as: Type A (spindle cell or medullary)—composed of a population of neoplastic thymic epithelial cells having a spindle or oval shape, lacking nuclear atypia, and accompanied by few or no nonneoplastic lymphocytes. Type AB—foci having the features of type A thymoma admixed with foci rich in lymphocytes. Type B1—resembling the normal functional thymus in that it combines large expanses having an appearance practically indistinguishable from normal thymic cortex with areas resembling thymic medulla. Type B2—the neoplastic epithelial component appears as scattered plump cells with vesicular nuclei and distinct nucleoli among a heavy population of lymphocytes. Perivascular spaces are common and sometimes very prominent. A perivascular arrangement of tumor cells resulting in a palisading effect may be seen. Type B3—predominantly composed of epithelial cells having a round or polygonal shape and exhibiting no or mild atypia. They are admixed with a minor component of lymphocytes, resulting in a sheet-like growth of the neoplastic cells. This histotype is synonymous with ‘‘well-differentiated thymic carcinoma,’’ as cited previously. Type C—thymomas that are outright thymic carcinomas, with obvious cytologic anaplasia.
Since the introduction of this system, several publications have claimed that the WHO classification is prognostic [27,57–60], even though it was not intended to be [61]. The author’s conclusions regarding that assertion are similar to those expressed earlier in regard to the MMH scheme. Another proposal appeared virtually simultaneously with the WHO monograph, and was advanced by Suster and Moran. It holds that thymic epithelial
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tumors can be divided into ‘‘thymomas’’ (corresponding to WHO type A, AB, B1, and B2 tumors), ‘‘atypical thymomas’’ (WHO type B3 lesions), and ‘‘thymic carcinomas’’ (PTCs, WHO type C tumors) [62,63]. The author strongly endorses that practical paradigm.
FORMAL STAGING OF THYMOMAS As show by the foregoing comments, the author does not subscribe to the purely-histologic prognostication of thymomas and continues to believe [64] that the best method for predicting the behavior of such tumors is through attention to their macroscopic growth patterns. This tenet is not new; it was first suggested by Bernatz and colleagues [20] and formalized later by Bergh and colleagues [65], Wilkins and Castleman [66], and Masaoka and colleagues [67]. The specific elements of staging schemes presented by those investigators are shown in Table 2 Among them, the Masaoka system, as advanced in 1981, has been used the most widely and tested the most extensively in clinical practice. It fundamentally separates those thymomas that are encapsulated from others that grow through the tumor capsule into surrounding soft tissue, from still other tumors that involve additional viscera. In the last of those categories, a stage-specific distinction, is made between lesions that infiltrate other organs by direct extension as opposed to true metastasis. Table 2 Comparison of Masaoka, Bergh, and Wilkins-Castleman staging systems for thymoma Masaoka system [67]
Bergh system [65]
Wilkins-Castleman system [66]
Stage I—Macroscopically and microscopically completely encapsulated Stage II—Macroscopic invasion into surrounding fatty tissue or mediastinal pleura (stage IIb) or microscopic invasion into the capsule (stage IIa) Stage III—Macroscopic invasion into adjacent organs or intrathoracic metastases Stage IVa—Pleural or pericardial implants or dissemination Stage IVb—Nodal or hematogenous metastases
Stage I—Intact capsule or tumor growth within the capsule Stage II—Pericapsular tumor growth into mediastinal fat
Stage 1—Intact capsule or tumor growth within the capsule Stage II—Pericapsular tumor growth into mediastinal fat, adjacent pleura, or pericardium
Stage III—Invasive tumor growth into surrounding organs or intrathoracic metastasis
Stage III—Invasive tumor growth into surrounding organs or intrathoracic metastasis
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In the original publication by Masaoka and colleagues [67], several conclusions were made in a thorough study of 96 thymomas that had been treated at one institution in Japan. Those conclusions are the following: Complete excision of thymoma was the single most optimal therapeutic measure, even if it required en bloc removal of a significant portion of the perithymic soft tissue or an adjacent organ, such as the lung; Radiotherapy for invasive tumors appeared to hinder their local recurrence; A statistically significant difference could be demonstrated in the survival of patients with stage I (gland-confined) tumors, as compared with others who had stage III or stage IV thymomas (involving regional structures) (Fig. 1); and Stage IVb (metastasizing) tumors were rare, comprising only 3% of all thymomas.
In the intervening 26 years, the validity of these statements has been affirmed and they have been used to structure predefined therapeutic approaches for thymoma. For example, chemotherapy—sometimes with irradiation as well—is currently given routinely to patients with stage III or stage IV thymomas (Figs. 2 and 3), usually in a neoadjuvant setting [34,68–70]. The management of stage II lesions (Fig. 4) is more controversial at present. Although some studies continue to advocate the use of irradiation for that group [71], the latter treatment is inconsistently used and may not be necessary [72–75]. The author’s own meta-analysis of the literature on stage II thymomas indicates that their overall prognosis is not significantly different from that of stage I tumors (Fig. 5), with or without radiotherapy [76]. Two other controversial points that are tied to stage-based therapy relate to unequivocally aggressive thymic epithelial tumors. Stage IVa lesions—which involve the pleural surfaces, or pericardium, or both—have been managed in some small series with pleuropneumonectomy and pericardiectomy. Some investigators have advocated this approach, together with preoperative and postoperative chemotherapy [77], whereas others have denigrated it as ineffective
Fig. 1. Survival curve for thymomas studied in the original series by Masaoka and colleagues, as divided into four strata. (Data from Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48:2485–92.)
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Fig. 2. Histologic image of Masaoka stage III thymoma, demonstrating tumor (upper left) directly invading lung parenchyma (hematoxylin and eosin stain 200).
or even harmful [78]. In similar counterpoint, Masaoka staging has been variously supported [29,79] or opposed [80] as a prognostic tool for PTCs. The Groupe d’Etudes Des Tumeurs Thymiques Modification of the Masaoka Staging System for Thymoma In the late 1980s, the Groupe d’Etudes des Tumeurs Thymiques (GETT; French Study Group on Thymic Tumors) initiated the construction of a derivative Masaoka staging system that was principally tied to surgical therapy for thymomas (Table 3) [81,82]. The resulting GETT scheme has been tested clinically in the interim and found to perform well in a predictive fashion [36]. Tumor-Nodal-Metastasis Staging of Thymoma and Thymic Carcinoma In an attempt to conform with the staging systems for various malignancies that have been advanced by the American Joint Committee on Cancer, Yamakawa and colleagues [83] also suggested using a TNM (tumor substage-nodal statusmetastasis) scheme for the staging of thymoma. That proposal was followed
Fig. 3. Two Masaoka stage IV thymomas. (A) This Masaoka stage IVa thymoma shows obvious growth around the great mediastinal blood vessels and involvement of the right pleura in a computed tomogram. (B) Another case of thymoma demonstrates multifocal embolic metastasis to the lung parenchyma in a computed tomogram, establishing a Masaoka stage of IVb.
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Fig. 4. Masaoka staged thymomas. (A) This computed tomogram demonstrates a thymic mass with only questionable involvement of the adjacent mediastinal soft tissue. (B) An ‘‘extended’’ thymectomy specimen is shown here, demonstrating invasion of a thymoma into the mediastinal fat (Masaoka stage IIb). The final surgical margins were uninvolved. (C) This thymoma shows microscopic invasion into, but not through, the fibrous tumor capsule (Masaoka stage IIa) (hematoxylin and eosin stain 200). (D) A mushroom-shaped protrusion of tumor is seen breaching the fibrous tumor capsule in this Masaoka stage IIb thymoma (hematoxylin and eosin stain 150).
several years later by a similar TNM paradigm for PTC, as advanced by Tsuchiya and colleagues (Table 4) [84]. These propositions are problematic because their publication did not follow prospective trials to see whether their composite elements performed adequately in the clinical context of comparable treatment modalities. Moreover, to the best of the author’s awareness, the TNM substrata were created intuitively rather than being tied to a rigorous statistical modeling procedure. Thus, from the perspective of evidence-based medicine, one must be skeptical of their soundness unless and until the TNM systems for thymic tumors are tested systematically. Other Iterations of the Masaoka Staging System One of the most interesting permutations of the classic Masaoka scheme is that reported by Asamura and colleagues [85]. Those investigators constructed two testable staging systems in reference to patients with thymomas of different stages who had been treated at a single institution. Classic Masaoka stage I was combined with stage II to yield stage IA (for Asamura) in both proposed staging
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Fig. 5. Masaoka stage I thymoma. (A) An anterior mediastinal mass is present in this chest radiograph, projecting into the right hemithorax. Excision of the lesion demonstrated an encapsulated tumor with internal fibrous septa (B), representing a Masaoka stage I thymoma. (C) Microscopic examination of the lesion confirmed its containment by the fibrous capsule (hematoxylin and eosin stain 200); (D) it manifested histologic heterogeneity from region to region, but was generally epithelial-predominant (hematoxylin and eosin stain 400).
Table 3 Groupe d’Etudes des Tumeurs Thymiques staging system for thymoma Classification
Description
Stage IA Stage IB
Encapsulated, completely resected Macroscopically completely resected but suspicion of mediastinal adhesions or potential capsular invasion at surgery Invasive tumor, completely resected Invasive tumor, subtotal resection Invasive tumor, biopsy alone Supraclavicular or pleural metastasis Distant metastases
Stage Stage Stage Stage
II IIIA IIIB IVA
Stage IVB
Data from Gamondes JP, Balawi A, Greenland T, et al. Seventeen years of surgical treatment of thymoma: factors influencing survival. Eur J Cardiothorac Surg 1991;5:124–131.
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Table 4 Proposed TNM schemes for thymoma and thymic carcinoma Thymoma pT Substage pT1 pT2
Description Completely encapsulated tumor Tumor breaking through capsule, invading thymus or fatty tissue Tumor breaking through the mediastinal pleura or pericardium, or invading neighboring organs, such as great vessels and lung Tumor with pleural or pericardial implantation
pT3
pT4 pN Substage pN0 pN1 pN2
No lymph node metastasis Metastasis in anterior mediastinal lymph nodes Metastasis in intrathoracic lymph nodes excluding anterior mediastinal lymph nodes Metastasis in extrathoracic lymph nodes
pN3 pM Substage pM0 pM1 Thymic carcinoma pT Substage pT1 pT2
No distant organ metastasis With distant metastasis
Completely encapsulated tumor Tumor breaking through capsule, invading thymus or fatty tissue Tumor breaking through the mediastinal pleura or pericardium, or invading neighboring organs, such as great vessels and lung Tumor with pleural or pericardial implantation
pT3
pT4 pN Substage pN0 pN1
No lymph node metastasi Metastasis in anterior mediastinal lymph nodes Metastasis in intrathoracic lymph nodes excluding anterior mediastinal lymph nodes Metastasis in extrathoracic lymph nodes
pN2 pN3 pM Substage pM0 pM1 Primary tumor Stage I Stage II Stage III Stage IVa Stage IVb Stage IVc
No distant organ metastasis With distant metastasis T1, T2 T1, T2 T3 T4 any T any T
Lymph node status N0 N1 N0, N1 N0, N1 N2, N3
Distant metastasis M0 M0 M0 M0 M0
Data from Yamakawa Y, Masaoka A, Hashimoto T, et al. A tentative tumor-node-metastasis classification of thymoma. Cancer 1991;68:1984–7; and Tsuchiya R, Koga K, Matsuno Y, et al. Thymic carcinoma: proposal for pathological TNM staging. Pathol Int 1994;44:505–12.
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schemes. Stages II and III tumors were defined as invasive thymomas, with varying combinations of tumor diameter, and involved adjacent structures, as represented in the two proposed systems. In the first of these, ‘‘Scheme 1’’, stage IIA lesions were defined as masses up to 10 cm in maximal dimension and involving no more than one regional structure or organ. Stage IIIA neoplasms were represented by lesions of all sizes that involved more than two regional structures or organs. In ‘‘Scheme 2,’’ stage II thymomas were lesions of all sizes that involved only one regional structure or organ, and stage III tumors were greater than 10 cm in maximal size as well as involving more than two adjacent structures or organs. Comparisons of case outcome were done according to the classic Masaoka staging system, and Schemes 1 and 2 of Asamura and colleagues. Survival curves for Asamura Scheme 1 yielded the most balanced distribution of patients in each staging group. These data further support the merging of classic Masaoka stages I and II, and they indicate that tumor size and a codified extent of regional growth add further discrimination to staging. CURRENT METHODOLOGIC PROBLEMS IN STAGING THYMIC NEOPLASMS Definitive treatment for thymic epithelial tumors has been predicated in an attempt at their complete surgical removal; in most medical centers, that statement still pertains [86–89]. Surgical exploration and resection allows for direct visualization of tumor growth by the surgeon and the pathologist, and many publications have attested to the survival-advantage of excising all grossly-visible disease [28,70–72]. Admittedly, problems may arise in distinguishing true invasion from fibrous adhesions between thymomas and adjacent structures. However, the author believes that it is much better to visually inspect the areas in question and biopsy them when possible, than it is to rely on imaging studies to define invasive growth. Hence, formal therapeutic thoracotomy, or alternatively, thoracoscopy and multifocal excisional biopsies, should be the initial steps in the clinical staging
Fig. 6. This fine needle aspiration biopsy of a thymic mass shows large loosely cohesive epithelioid cells admixed with lymphocytes, consistent with the cytologic image of thymoma. That impression was confirmed by positive immunostaining for pankeratin, p63, and CD99. (Papanicolaou stain 400).
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of thymic epithelial lesions. That is true even for those thymomas that are felt to be stage III or stage IV neoplasms at presentation. Over the past 15 years, an increasing trend has appeared toward establishing a pathologic diagnosis of thymoma using very small tissue samples (eg, by fineneedle aspiration biopsy shown in Fig. 6 [90] or cutting-needle-core biopsy) and immunohistology or electron microscopy [91]. Thereafter, the results of imaging studies are often used to stage the tumor and guide nonsurgical therapy. This approach is generally acceptable, but it does have several distinct drawbacks. First, cases are encountered in which pleural or pulmonary lesions are felt to represent high-stage metastatic disease radiographically, but are subsequently shown to be nonneoplastic or nonthymic after eventual tissue sampling is done. In those circumstances, the risk of morbid over-treatment is a real one. Secondly, the radiographic separation of stage I from stage II thymomas is imprecise [34], even with high-resolution computed tomography or magnetic resonance imaging [92–94]. Admittedly, that problem may well be moot in light of the comparable biologic behavior of those two tumor groups. Finally, Suster and Moran [63,95] have shown that some thymomas undergo clonal evolution to yield areas of PTC in the same mass. The latter foci may easily be missed in small biopsy samples [55]. Thus, clinicians caring for patients with thymic neoplasms must recognize that nonpathologic staging procedures may be associated with problematic responses to treatment or an unexpected clinical evolution. In that eventuality, tissue procurement from indeterminate clinical or radiographic lesions is advisable to clarify the situation. The staging of de novo PTCs is problematic under any circumstance. Along with Blumberg and colleagues [80], the author believes that neither the GETT nor the Masaoka systems reliably predict the evolution of such tumors. For example, the author has seen several completely encapsulated PTCs that metastasized widely. Until another tenable paradigm for prognosticating such tumors is compiled, one must assume that most thymic carcinomas have a definite potential for both local recurrence and distant metastasis [13,14,96–100] and treat patients accordingly. The only exceptions to that statement concern rare lowgrade PTCs, such as basaloid carcinoma, mucoepidermoid carcinoma, and well-differentiated encapsulated squamous-cell carcinoma [14,101]. References [1] Binkley FM, Thorburn JD, Stephens HB, et al. Mediastinal tumors of thymic origin. Calif Med 1953;78:267–73. [2] Soutter L, Sommers S, Relman AS, et al. Problems in the surgical management of thymic tumors. Ann Surg 1957;146:424–37. [3] Sellors TH, Thackray AC, Thomson AD. Tumors of the thymus. Thorax 1967;22:193–221. [4] Lowenhaupt E. Tumors of the thymus in relation to the thymic epithelial anlage. Cancer 1948;1:547–63. [5] Rosai J, Levine GD. Thymic hyperplasia and neoplasia: a review of current concepts. Hum Pathol 1978;9:495–515. [6] Lewis JE, Wick MR, Scheithauer BW, et al. Thymomas: a clinicopathologic review. Cancer 1987;60:2727–43.
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