Thymomas have long attracted interest for a number

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1 Clinical Value of the WHO Classification System of Thymoma Frank C. Detterbeck, MD Division of Thoracic Surgery, Yale University, New Haven, Connecticut Since the World Health Organization (WHO) histologic classification system for thymoma was introduced in 1999, several centers have published results using this system. This review of the published experience with the WHO system examines whether the classification is reproducible, whether the WHO system defines clinically distinct patient groups, assesses the independent prognostic value of the WHO type by multivariate analysis, and discusses the impact of the WHO system on clinical management decisions. (Ann Thorac Surg 2006;81: ) 2006 by The Society of Thoracic Surgeons Thymomas have long attracted interest for a number of reasons. These tumors have an indolent course, but nevertheless all have the ability to invade and metastasize that characterizes malignant tumors. The pattern of spread is unusual, however, with a high prevalence of pleural and pericardial nodules. Thymomas are commonly associated with parathymic syndromes, which are generally autoimmune diseases, the most common being myasthenia gravis (MG) [1]. Thymomas also have held the interest of pathologists owing to their varied appearance and the frequent lack of classic malignant features. In fact, at one time, some thymomas were mistakenly classified as benign thymomas, a term that has been largely discarded because recurrences have been observed for every stage and histologic subtype of thymoma [1]. Many different histologic classification systems have been proposed and used. Initial reports with earlier classification systems suggested clinical utility to each newly proposed system. However, more widespread experience and multivariate analysis indicated that the ability to distinguish clinically distinct patient cohorts was limited, and the independent prognostic value of the earlier systems was questionable at best. Furthermore, questions arose regarding the interobserver reproducibility of the classification. Thus, although these systems described the microscopic appearance of these tumors, their clinical value left room for improvement. The most recent classification system was proposed in 1999 and updated in 2004 by an international committee of experts assembled by the World Health Organization (WHO) [2, 3]. In recent years, several larger centers have published the results of their experience with the new system [4 12]. It therefore seems appropriate at this time to review these data to assess the clinical value of the new system. This article is an attempt to accomplish this, given the data available as of April Address correspondence to Dr Detterbeck, Division of Thoracic Surgery, FMB 128, 330 Cedar St, Yale University, New Haven, CT ; frank.detterbeck@yale.edu. Any classification system is inevitably expected to satisfy the needs of many people with different viewpoints, which may be quite distinct from the intended purpose of those developing the system. This paper takes primarily a clinical viewpoint. General questions are addressed such as whether the WHO classification system is reproducible or whether it defines patients with distinct clinical features (demographics, presentation) suggestive of a distinct etiology. However, the major focus is on whether the WHO histologic classification system can predict the clinical course of patients, and how it can be used in the clinical management of patients. Historical Histologic Classification Systems One of the earlier histologic classification systems of thymomas that was widely used, by Bernatz and colleagues [13], recognized four categories, based on the predominant (more than 66%) cell type: lymphocytic, epithelial, mixed epithelial and lymphocytic, and spindle cell types. However, there was poor correlation with prognosis, and as thymomas are tumors of the thymic epithelial cell, classification based on the number of lymphocytes seems scientifically unfounded. The classification system of Verley and Hollmann [14] also considered four types: spindle or oval cell, lymphocyte rich, differentiated epithelial cell rich, and undifferentiated epithelial cell tumors. The first three of these types encompassed the vast majority of thymomas, which are cytologically bland, while the fourth category included the pleomorphic tumors with the mitoses and atypia that have also been called thymic carcinoma. This classification scheme suffers from the same criticism raised above. A classification system proposed by Müller- Hermelink and associates [15] is based on the fact that the thymus contains different subsets of epithelial cells. In this system, thymomas are classified as cortical, medullary, and mixed cortical and medullary types (with either cortical or medullary predominance) and 2006 by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg DETTERBECK 2006;81: WHO CLASSIFICATION OF THYMOMA 2329 well-differentiated thymic carcinoma [15]. However, studies have shown inconsistent correlation of these types of thymoma with the types of thymic epithelial cells from which they are thought to arise [16]. Furthermore, a relationship between these histologic types and prognosis has been inconsistent [16 19], and the histologic type is not an independent predictor of survival in multivariate analysis [17, 20, 21], with the exception of one smaller study [22]. Well-differentiated thymic carcinoma is a controversial group, with organotypical features of thymomas but also areas of atypia and mitoses (usually fewer than 2 per 10 high-power field) [1]. There is variability in the incidence and survival of this group [1]. On the other hand, thymic carcinoma is clearly recognized as a distinct group, with a virtual absence of parathymic syndromes, clear-cut cellular atypia, and a very poor prognosis [1]. Thymic carcinoma has been divided into subtypes, including squamous cell, mucoepidermoid, basaloid, lymphoepitheliomalike, small cell/ neuroendocrine, sarcomatoid, clear cell, and undifferentiated/anaplastic [23]. Thymic carcinoid tumors have generally been classified as a separate type of thymic tumor, although they have recently been referred to as a neuroendocrine thymic tumor because of the presence of neuroendocrine granules, which is a feature they share with many thymic carcinomas. Attempts to correlate the classification of tumors in one of these systems to that of another have revealed no particular correlation [16]. An exception is that most spindle cell tumors are classified as medullary tumors in the Müller-Hermelink method (but not vice versa) [16, 24, 25]. Furthermore, there is often marked variability in the morphologic appearance even within the same tumor [26 28]. Finally, when thymomas are classified independently by a panel of pathologists using these systems, thymomas are assigned to the same group in only a minority (35%) of cases [27], although another such study, which used the Müller-Hermelink classification system, found concordant classification in 78% of 51 cases [29]. These issues are reflected in the marked variation of the reported incidence of the different histologic types (for example, medullary 5% [30] to 22% [17], cortical 10% [30] to 41% [17], spindle cell 4% [25] to 23% [31], and epithelial 5% [31] to 28% [25], among large series). A simpler classification system was proposed by Suster and Moran [32] in 1999, distinguishing thymoma, atypical thymoma, and thymic carcinoma primarily by the degree of cellular atypia. These three categories were suggested to correspond to the large group of cytologically bland thymomas, well-differentiated thymic carcinoma, and thymic carcinoma with overt cytologic malignant features, respectively. The prognostic relevance of the threegroup classification of Suster and Moran has not been widely studied. This may be because that same year, the WHO classification system was published [2] (see next section). Description of WHO System The WHO classification system [2] bears some similarities to the Müller-Hermelink system but recognizes six different types of thymic tumors (types A, AB, B1, B2, B3, and C). Type A tumors are composed of neoplastic oval or spindle-shaped epithelial cells without atypia or lymphocytes. Type AB is similar to type A, but has foci of lymphocytes. Type B tumors consist of plump epithelioid cells and are subdivided into three subtypes as defined by an increasing proportion of epithelial cells and increasing atypia. Type B1 tumors resemble normal thymic cortex with areas similar to thymic medulla. Type B2 have scattered neoplastic epithelial cells with vesicular nuclei and distinct nucleoli among a heavy population of lymphocytes; perivascular spaces are prominent and a palisading effect of tumor cells along the perivascular spaces may be seen. Type B3 is composed of predominantly round or polygonal epithelial cells exhibiting mild atypia admixed with a minor component of lymphocytes; thus, this type resembles what others have described as well-differentiated thymic carcinoma. Thymic carcinomas are designated as type C tumors; these have clearcut cytologic atypia and a cytoarchitecture resembling carcinoma and dissimilar to the thymus. Material and Methods Articles were searched using the Medline database and the terms thymoma or thymic tumors. The abstracts of all such articles from January of 1999 through April of 2005 were reviewed, and all articles in which there was any indication of addressing the value of the WHO classification were selected for a complete review. Relevant articles were selected if a multivariate analysis of outcomes was carried out that included the WHO classification system. Only articles published or presented in English were considered. That was due partly to practical considerations, but mostly to the observation in the lung cancer literature that significant foreign language articles are almost invariably also published in English either in duplicate or with additional data or patients. Results Is the WHO Classification System Reproducible? In general, the concordance of classification using the WHO system among different pathologists appears to be relatively good. Two studies have reported a concordance rate of 90% and 95% [9, 11], although the analysis appears not to have been done in a strictly rigorous fashion, and the classification among the two reviewers was not completely independent. A more rigorous study of 218 cases indicated a kappa statistic of 0.87 (very good concordance) for all WHO groups [33]. However, there was a fair amount of inconsistency in classification of the B subtypes, with a kappa statistic of only 0.47 among the B subgroups [33]. The difficulty in classification of B subtypes is corroborated by the variable proportion of combination types (3% to 21%), which have generally in-

3 2330 DETTERBECK Ann Thorac Surg WHO CLASSIFICATION OF THYMOMA 2006;81: Table 1. Incidence of Histologic Classes of Thymomas n Percent of All Thymomas Ströbel [8] b Okumura [5] Rieker [33] Chen [11] Wright [10] a Park [9] Rea [12] Nakagawa [6] c c Kim [36] Kondo [7] Chalabreysse [4] Average a Only resected patients. carcinoma was included. b Only the squamous cell type of thymic c Type C excluded. volved combinations of B2/B3 subtypes (and less frequently B3/C or AB/B2 combinations) [7 9, 11]. Comparison of the proportion of WHO subtypes across studies also suggests some difficulty with consistent classification (Table 1). The variable proportions of WHO subtypes are not restricted to the B subtypes, but are seen in all subtypes. The proportion of type A varies from 4% to 20%; for AB, from 9% to 43%; for B1, 6% to 27%; for B2, 8% to 38%; for B3, 5% to 29%; and for C, 2% to 28%. All of these studies were quite large, making it difficult to ascribe this to chance alone. Furthermore, it seems unlikely that differences in referral patterns between centers could account for the variability, as there is no apparent pattern that appears to explain it (for example, the proportion of patients with MG). Does the WHO System Describe Clinically Distinct Patient Cohorts? The available data on the clinical characteristics of patients with thymomas of a particular WHO type are shown in Table 2. The median age appears to be higher among patients with a type A thymoma, intermediate for type AB, lower for patients with a B subtype, and higher again for patients with a type C thymoma. Furthermore, fewer than half of patients with types A-B2 thymoma are male, whereas the majority are male for types B3 and C. Myasthenia gravis is less frequent for types A and AB, fairly common in the B types, and distinctly absent in type C. There is a marked variability across studies, however, especially with regard to the proportion of men and the incidence of MG. The incidence of MG varies from 0% to 29% for type A, 6% to 42% for type AB, 7% to 70% for type B1, 24% to 71% for type B2, and 25% to 65% for type B3, but is consistently low (0% to 3%) for type C. What is most striking about the clinical characteristics across published reports is the tight consistency among type C (average age of 57 years, two thirds male, and absence of MG), and the marked variability among the other groups. Before the WHO classification system, thymic carcinoma (WHO type C) was recognized as a distinct type of thymoma, with findings regarding age, sex, and MG very similar to the results in Table 2 [1]. Therefore, both the WHO classification system as well as previous classification systems consistently suggest that thymic carcinoma occurs in a distinct patient group. The marked variability in clinical characteristics of patients with other WHO types casts doubt on how well this system is able to describe clinically distinct patient cohorts, although some general trends are apparent. Studies involving the WHO system have all shown a marked correlation between the histologic type and the Masaoka stage (Table 3). The vast majority of type A and AB thymomas are stage I or II. However, there is some variability between studies, with stage III thymomas accounting for 0% to 13% of type A and 0% to 25% of type AB thymomas. A trend is also seen among B1, B2, and B3 subtypes toward an increasing number of stage III and IV thymomas. However, there is marked variability, with stage I ranging from 13% to 67% for B1, 7% to 56% for B2, and 0% to 42% for B3. Similarly, the proportion of stage IV patients ranges from 0% to 21% for B1, 0% to 24% for Table 2. Clinical Characteristics of Patients by WHO Type of Thymoma Age % MG Age % MG Age % MG Age % MG Age % MG Age % MG Ströbel [8] a 73 a 0 a Okumura [5] Chen [11] 25 b Park [9] 0 b Nakagawa [6] Kim [36] 59 b 0 b Kondo [7] 0 b b 50 0 Chalabreysse [4] 67 b 33 b 33 b Average a Only the squamous cell type of thymic carcinoma was included. b Groups with fewer than 10 patients. Age age at presentation in years; % percent male; MG percent with myasthenia gravis; WHO World Health Organization.

4 Ann Thorac Surg DETTERBECK 2006;81: WHO CLASSIFICATION OF THYMOMA 2331 Table 3. Correlation of Masaoka Stage and WHO Type of Thymoma I II III IV I II III IV I II III IV I II III IV I II III IV I II III IV Okamura [5] Rieker [33] Chen [11] 50 a 38 a 13 a Park [9] 57 a 43 a 0 a 0 a Nakagawa [6] Kim [36] Kondo [7] 50 a 50 a a 38 a 25 a Average a Groups with fewer than 10 patients. WHO World Health Organization. B2, and 8% to 50% for B3. The variability among type C thymomas is primarily confined to the relative proportions of stage III and IV thymomas. It is not clear that these data indicate that the WHO classification does or does not define distinct patient cohorts because of the confounding factor of potential differences in lead time (between development of the tumor and clinical recognition of it). Does the WHO System Predict the Clinical Course? The major purpose of a classification system is to predict the clinical course. Many factors have been found in individual studies to be of potential prognostic significance, but the most consistent ones are the Masaoka stage and the completeness of resection [1]. When multiple potential prognostic factors have been suggested, a multivariate analysis (MVA) is necessary to define which factors carry independent prognostic value, and which ones are merely associated with other, more important prognostic factors. That is especially true because the WHO type has been consistently correlated with the Masaoka stage. Therefore, MVA studies that omit stage are of questionable value. The results of all MVA studies involving WHO classification and stage are shown in Table 4. Whether completeness of resection was analyzed is shown as well, but other factors are omitted for clarity because they have only sporadically been found to be of prognostic value. Several additional studies involving MVA and the WHO classification were not included for the following reasons: three studies in which stage was excluded [4, 6, 11], a limited study involving only 14 patients with types B3 and C thymoma [34], and a study that reported that a multivariate analysis was done, but did not report the results thereof (with the exception that tumor recurrence was the single most important negative prognostic factor by MVA) [8]. The three studies that excluded stage implied that WHO would not be significant unless stage was excluded. In fact, one study excluded the stage because stage was the most significant predictor by MVA (p 0.003), in order to assess the independent predictive value of histology [11]. This argument seems to be a direct contradiction to the meaning of independent factors by MVA. The data in Table 4 generally demonstrate that the WHO type is of independent prognostic value, with the exception of the two smallest studies. In general [35], the stage appears to be a slightly more important factor as judged by the degree of statistical significance as well as by the magnitude of the odds ratio. Nevertheless, the WHO type does appear to have prognostic value above and beyond stage. Most of the studies listed in Table 4 Table 4. Multivariate Analysis of Factors Predicting Thymoma-Specific Survival Histology Stage R 0 n p Value OR p Value OR p Value OR Okamura [5] a NS Rieker [33] c d Wright [10] NS Park [9] b c d Rea [12] b NS Kim [36] 108 NS d NS Kondo [7] b 100 NS a Type C excluded. b Overall survival. c Odds ratio for type C. d Odds ratio for stage IV. NS not statistically significant; OR odds ratio; R 0 complete resection.

5 2332 DETTERBECK Ann Thorac Surg WHO CLASSIFICATION OF THYMOMA 2006;81: Fig 1. (A) Thymoma-specific survival according to the World Health Organization (WHO) histologic subtype A, AB, B1, B2, B3, and C in 218 patients. (From Histologic classification of thymic epithelial tumors: comparison of established classification schemes; Rieker et al; Copyright Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc [33].) (B) Thymoma-specific survival according the WHO histologic subtype A, AB, B1, B2, B3, and C in 108 patients. Tumor death defined as any death related to the thymoma, such as recurrence or myasthenia gravis [36]. have focused on disease-specific survival instead of overall survival, which is important because fewer than half of deaths are due to thymoma [1]. An even better indicator of prognosis may be the incidence of recurrence. Only two studies have carried out a MVA of recurrence that included the WHO classification [7, 10]. In both of these studies, the Masaoka stage was significant by MVA, whereas the WHO stage was significant in one but not the other. A closer look at the details of the studies raises some questions about the ability of the WHO system to predict prognosis of each of the subgroups. Some studies suggest the subtypes can be separated into two cohorts (but of differing compositions: A/AB/B1 versus B2,3/C in two studies [11, 12] and A/AB/B1-3 versus C in another [4]). Other studies (Fig 1a, b) find three prognostic clusters (but of differing compositions: AB versus A/B1-3 versus C [33] and A/AB/B1,2 versus B3 versus C [36]). Four cohorts are distinguished in other studies (again with differing compositions: A/AB versus B1,2 versus B3 versus C [7, 10] and A versus AB/B1,2 versus B3 versus C [9]). In addition, two studies that excluded type C suggest at least three (presumably four if type C was included) groups can be defined (but of differing compositions: A/AB/B1 versus B2 versus B3 [5] and A/AB versus B1,2 versus B3 [6]). The variability in how the subtypes are grouped is due to the fact that the survival of patients with the WHO subtypes varies significantly across studies (Table 5). The consistent finding among all studies is that type C exhibits a worse survival. There is at least a suggestion in many studies that type B3 has intermediate survival [7, 9, 10, 12, 36], although that is not borne out in others [4, 11, 33]. The survival of the other subtypes appears to be so inconsistent across studies that it appears questionable whether the WHO histologic subtypes can be used to predict outcomes or guide therapy for these cohorts (A, Table 5. Thymoma-Specific Survival by WHO Histologic Class of Thymoma Percent 10-Year Thymoma-Specific Survival a n Okumura [5] b Rieker [33] Chen [11] c e Wright [10] d Ströbel [8] f Rea [12] c Nakagawa [6] b Kim [36] e Kondo [7] d e e Average a Unless otherwise indicated. b Type C excluded. c Overall survival. d Disease-free survival. e Group with fewer than 10 patients. f Only the squamous cell type of thymic carcinoma was included. WHO World Health Organization.

6 Ann Thorac Surg DETTERBECK 2006;81: WHO CLASSIFICATION OF THYMOMA 2333 AB, B1, B2). Thus, a closer look at the WHO subtypes suggests that only a grouping of thymoma versus thymic carcinoma is clearly supported (similar to the 1978 category I and II classification of Levine and Rosai [37]), and a three-tiered classification is probably supported (similar to the 1999 system of Suster and Moran [32], distinguishing thymoma, atypical thymoma and thymic carcinoma). How Do We Use the WHO System to Guide Clinical Management? The clinical value of the WHO classification is primarily determined by whether the information gained affects clinical management. The primary decision to be made in the treatment of thymoma is whether to administer preoperative chemotherapy. There is an increasing amount of phase II data that suggest that this is beneficial for stage III and perhaps also for stage IVa thymomas [1]. The role of chemotherapy for stage II thymoma remains undefined, but given the good results with surgery alone, this appears to be unlikely to be of benefit in general. Postoperative radiotherapy has little role in completely resected tumors, but is probably of benefit in incompletely resected tumors (usually stage III and IVa tumors) [1, 38 40]. Of course, the decision whether to undertake a resection must also be made, but at this time, that remains primarily a technical and surgical issue as to whether one can achieve a complete resection [1]. If WHO type is going to be helpful, it is therefore most likely in the definition of whether to give preoperative chemotherapy, and less so whether to give adjuvant radiotherapy or whether to undertake a resection. It is unclear at this time how the WHO classification influences clinical management. First of all, there are no data on how reliably the WHO type can be determined from a pretreatment needle or incisional biopsy. There is at least some doubt about this, given the data cited above on the disagreement between pathologists over resected specimens. Furthermore, even if the WHO type can, in fact, be determined preoperatively, it is unclear how this should influence management beyond what is already defined by the stage. Whether a pretreatment diagnosis of a type A or AB stage III or IV thymoma should be used to avoid preoperative chemotherapy is unknown. Given the proportions of type A, AB thymoma that present as stage III or IV, this issue will affect only a small proportion of patients. Similarly, whether a preoperative diagnosis of a type B3 or C stage I or II thymoma should cause us to give chemotherapy has not been addressed in the literature. Again, such a situation would be quite rare. The decision regarding postoperative radiotherapy should be determined by the completeness of resection. Whether the WHO type should influence this decision as well has not been studied. There are no data, even from retrospective series, that address the role of adjuvant chemotherapy. Therefore, it is difficult to make an evidence-based argument for the use of postoperative chemotherapy, or how the WHO type should influence this. Comment The WHO classification system appears to correlate with general trends in the clinical characteristics of patients. However, the variability in many aspects casts some doubt onto how clearly distinct patient cohorts are defined by this system (with the exception of type C). Similarly, although the interobserver reliability of the classification appears to be generally very good, the variability of the proportion of subgroups and the published difficulty in consistent classification of some subgroups suggest that there is room for improvement. The WHO classification system does appear to be an independent predictor of clinical course, but examination of the published survival curves suggests that this is primarily due to type C having distinctly worse survival. Whether so-called well-differentiated thymic carcinoma (type B3) defines a consistent cohort with a distinct prognosis is less well defined. The ability of the WHO classification to predict a distinct prognosis for the other subtypes (A, AB, B1, B2) is unclear. Finally, how the knowledge of the WHO subtype should be used clinically is unclear. Most treatment decisions appear to be guided by the clinical stage as assessed by imaging studies (or postresection stage when available), as well as the completeness of resection. Basing treatment decisions on the clinical stage has the advantage that it can be assessed noninvasively by imaging studies, whereas determination of the WHO subtype preoperatively requires a biopsy, the reliability of which for determining the histologic subtype has not been defined. However, no studies have addressed how reliably the stage of a thymoma can be determined from preoperative imaging studies either. That should be the focus of future research studies. Similarly, future studies to assess how reliably the WHO type can be determined before resection are needed. Finally, prospective studies would be useful addressing whether the WHO type is useful in clinical management decisions. Prospective outcome studies are somewhat impractical, however, given the indolent nature of many thymomas and the prolonged follow-up needed. Conclusions The WHO classification system does appear to be an advance in our understanding of thymoma. The classification is reasonably reproducible, and general trends toward different clinical characteristics of the patients of a particular subtype are suggested. It is most clear and consistent that type C (thymic carcinoma) is a distinct group. Similarly, the prognosis of this group (type C) is consistently distinct, and appears to account to a large extent for the finding that in general the WHO classification has independent prognostic value in addition to stage. However, the prognosis of other subtypes (A, AB, B1-3) is variable. Furthermore, how the WHO classification should be used clinically is unclear. The value of histologic classification remains primarily in distinguishing thymic carcinoma, and less clearly perhaps, welldifferentiated thymic carcinoma from other types of thy-

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