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Problems in the classification of thymoma
MINI-SYMPOSIUM: PATHOLOGY OF THE MEDIASTINUM
Problems in the classification of thymoma
letters and numbers to identify various histologic types of thymoma.1 This WHO classification of tumours of the thymus has been widely embraced by pathologists worldwide and has received the enthusiastic support of the establishment. Yet, some nagging issues continue to linger which begs the question: is this classification ideal and is there still room for improvement? In this review, we will briefly examine some of the controversial issues surrounding the current WHO classification of tumours of the thymus, including issues of reproducibility, interobserver variability, clinical significance of the various subtypes, and the biological rationale that supports the current classification scheme. The purpose is not to be critical simply for the sake of argument, but to offer constructive criticism and frame the issue in its proper perspective, i.e., what is best for the patient, so that appropriate adjustments and improvements can be made.
Saul Suster Cesar A Moran
Abstract The histologic classification of thymoma has posed difficulties for pathologists for many years and continues to be a focus of controversy in the speciality today. In recent years, the World Health Organization (WHO) has assembled a panel of experts with the purpose of devising a histologic classification system of thymoma that will be widely adopted for common use by pathologists and clinicians throughout the world. This objective has been largely accomplished with the introduction of the WHO histologic classification of tumours of the thymus. Despite the widespread acceptance of this classification, however, several controversial issues have remained unaddressed that still require attention. Herein we review briefly some of the issues that pose a challenge and require improvement in our current classification of thymomas, including issues related to ease of applicability of this classification and interobserver reproducibility in daily practice, the lack of a unifying, underlying biologic principle, the limitations for the stratification of patients for clinical management and the accuracy of some of the assumptions behind the definitions for some of the different proposed histologic types.
Biological basis of classification Setting aside classification schemes for thymoma that pre-date the one proposed by Bernatz et al. 2 in 1961from the Mayo Clinic, all subsequent modern schemes have been based on morphology and have not managed to provide a clear advantage over any of its competitors. The Bernatz et al. 2 schema, which was based on an earlier proposal by Dr. Rafaelle Lattes from Columbia University in New York,3 relied on the shape of the proliferating epithelial cells and the relative proportion of intratumoural lymphocytes for separating these tumours into four categories. This was an admittedly purely morphological classification whose main value resided in identifying the main prototypical histologic variants of thymoma for proper identification and to avoid misdiagnosing them for other conditions. However, it was acknowledged by the authors early on that the various histologic types did not correlate well with prognosis, and that the staging of the tumours constituted the most reliable tool for assessing their clinical behaviour.4 Subsequent thymoma classification proposals from Japan and France5,6 were also based on morphology and also lacked a unifying biologic basis. An apparent major breakthrough occurred in 1985 with the introduction of a new classification approach for thymoma introduced by Drs. Marino and MullerHermelink.7 Succinctly stated, their proposal claimed that thymomas were either derived from the cortex or the medulla of the thymus, with allowances for the existence of hybrid or ‘‘mixed’’ tumours showing an admixture of the two. Thus, thymomas were designated as of cortical, medullary or mixed type. This was the first time that a plausible histogenetic basis was ascribed to thymoma, and the proposal was dubbed the ‘‘histogenetic’’ classification. Predictably, this novel proposal was enthusiastically received by pathologists worldwide and gained wide acceptance and popularity. Over time, however, the complexity of the situation and the limitations for applying this schema became increasingly apparent to the authors and they had to admit that their proposed categories were not sufficient to explain the entire spectrum of observed thymic tumours. Thus, in 1989, a revised classification was presented by Kirschner and Muller-Hermelink8 that added two new categories to the previous schema; predominantly cortical (or ‘‘organoid’’) thymoma and ‘‘well-differentiated thymic
Keywords classification; thymic carcinoma; thymic epithelial neoplasm; thymoma
Introduction The classification of thymoma has been a controversial issue for many years. A large number of classification schemes have been presented over the years with varying rates of acceptance and success for applying them to clinical practice. Although all of the proposed schemas managed to accrue a loyal following and were indeed helpful as a guide for pathologists, none of them really managed to fulfil all of the intended requirements that a histopathologic classification of tumours should provide. For a histologic classification of any family of tumours to fulfil its role in the practice of medicine, it must be simple to understand, reproducible, and convey clinically relevant and significant information that rests on a solid biological basis. The latter characteristic, in particular, has consistently plagued and eluded classification systems of thymoma. In recent years, a panel of experts appointed by the WHO has devised a classification system that is based on a combination of
Saul Suster MD is Professor and Chairman, at the Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. Conflicts of interest: none. Cesar A Moran MD is Professor of Pathology at the University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. Conflicts of interest: none.
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carcinoma’’. Despite the great success and acceptance of the ‘‘histogenetic’’ classification, the biological underpinnings of this proposal were questioned by some. From a purely morphologic perspective, the morphotypes assigned to the different histogenetic designations appeared to be somewhat arbitrary and conflicted with the histologic appearance of the tumours. For example the tumours designated as ‘‘medullary’’ were those characterized by a predominant spindle cell population with paucity of lymphocytes. In traditional morphology, descriptive terms that allude to normal anatomic structures are expected to relate to processes that closely resemble histologically such normal structures. In the case of ‘‘medullary’’ thymoma, the dense spindle cell proliferation ascribed to such tumours did not even remotely resemble the normal medulla of the thymus (Figure 1). In fact, it was pointed out by Dr. Rosai in the initial WHO monograph9 that, if anything, the spindle cells in ‘‘medullary’’ thymoma most closely resembled the ‘‘effete’’, involuted thymic epithelial cells observed in thymic remnants of adults rather than the normal thymus medulla. The ‘‘mixed’’ tumours in the ‘‘histogenetic’’ classification also comprised a heterogeneous group that was difficult to define. In fact, the tumour designated by the authors as ‘‘predominantly cortical’’ was the only morphologic type of thymoma in their schema that could properly be categorized as ‘‘mixed’’ from a purely histogenetic point of view because it is the only type of thymoma that is truly composed of an admixture of well-developed and recognizable cortical and medullary areas that faithfully recapitulate these structures in the normal functional thymus (Figure 2).8 Further evidence to support the validity of the ‘‘histogenetic’’ proposal was sought from the immunohistochemical characterization of the cell phenotype in these tumours. Various attempts at analysing the subtypes of these tumours for various putative specific markers were made with little success. In fact, it was the authors of the ‘‘histogenetic’’ classification themselves who, with impeccable scientific integrity, acknowledged that .‘‘Using specific
Comparison of ‘‘predominantly cortical’’ thymoma with normal thymus: a predominantly cortical thymoma showing well-defined cortical zones admixed with well-defined medullary areas containing Hassall’s corpuscles; b normal mature functional thymus in a 10-year-old boy showing close resemblance to ‘‘a’’, with a welldeveloped cortex and medulla. Figure 2
monoclonal antibodies, specific immunophenotypes of the different histological tumor types cannot be defined. Therefore, presence or absence of reactivity with one of these monoclonal antibodies does not allow clear immunohistochemical differentiation between the different tumor types. Furthermore, the immunophenotype of the epithelial neoplastic cells cannot be strictly correlated to the immunophenotype of different epithelial cells in the thymus’’.8 Because of the confusion that still lingered around the histologic classification of thymoma, when the World Health Organization (WHO) was preparing to launch its second series of books devoted to the histologic classification of tumours, they invited Juan Rosai to assemble an international panel of experts to devise a definitive histologic classification of thymoma. The results of the panel’s deliberations led them to the realization that none of the existing classifications truly fulfilled all the requirements to enjoy universal acceptance. This led to the proposal for devising a schema that was based on a combination of letters and numbers that would allow authors using different terminologies to find a common designation for some of the most common morphologic types of thymoma. This new proposal became the first WHO classification of thymic tumours which was formally published in 1999.9 Once again, this new proposal by the WHO lacked a unifying scientific explanation for the various histologic types and was also based on morphology, relying on the same principles as the previous Bernatz et al. classification2 for separating thymomas based on their cell shape (round/plump/epithelioid vs. spindle/oval) and on their relative proportion of intratumoural lymphocytes. Thus, thymomas were said to be of two basic types, those predominantly composed of spindle/oval cells were designated as type A (equivalent to the spindle cell thymoma of Bernatz and to ‘‘medullary’’ thymoma of the ‘‘histogenetic’’ classification), and those composed of plump/ epithelioid cells were designated as type B (equivalent to
Comparison of ‘‘medullary’’ thymoma with the normal medulla: a ‘‘medullary’’ thymoma predominantly composed of a bland spindle cell population; b normal medulla in a functionally mature thymus. Figure 1
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staunchly defended over the past few years. Objections have been expressed to the effect that using letters and numbers goes against the established precedent of designating tumours in a more informative way using terms that will intuitively guide our clinical colleagues to an understanding of the nature of the process. Such objections have been countered by the anecdotal information provided by the WHO proponents that clinicians and surgeons ‘‘love’’ this terminology and are very happy with it. For an inquisitive mind, the use of various letters and numbers in a classification implies the existence of a strict rationale behind it; i.e., if there is a type B1eB2eB3, why aren’t there corresponding type A1eA2eA3? If there is a type AB, why isn’t there a type AC and BC? In fact, given the absence of an underlying theme or biologic explanation for the letters and numbers, wouldn’t it be simpler and more straightforward to simply designate these tumours as type 1 through 6 or A through F? What is the rationale and where is the need for the added complication behind the various letters and numbers? The justification that has been put forth by the WHO is that the different subtypes show a good correlation with the clinical behaviour of the lesions. Although a clinical correlation with the biologic behaviour of the tumours was not part of the original proposal presented by Dr. Rosai in 1999,9 the current WHO book claims that thymomas of type A and AB are benign, type B1 is a low-grade malignancy, type B2 is characterized by a ‘‘greater degree’’ of malignancy, and type B3 (in advanced stages) is equivalent to thymic carcinoma.1 This opinion is based on a single study by Prof. Muller-Hermelink and colleagues in 200 patients from China.10 The results of their study illustrated in the WHO book show a survival curve with a nice stepwise progression for these tumours from thymoma type A through B3. The problem is that this data has not been validated by other studies. A study by Chalabraysse et al. from France11 published the same year applying the WHO classification showed a worse prognosis for type A and AB tumours than for the type B tumours. Another multi-centre study from Germany published the same year showed essentially overlapping survival curves for patients with type A and B2 tumours.12 Another study from Japan, also published the same year, showed a better survival for patients with B1 thymoma than for type AB thymoma.13 Moreover, the contention by the WHO that type A thymoma is benign is in stark conflict with a large body of literature that has documented aggressive behaviour and tumour deaths in patients with spindle cell thymoma (WHO type A).2e6,11,12,14e16 The justification for using the combination of letters and numbers proposed by the WHO to designate these tumours based on their progressive correlation with an aggressive patient outcome is therefore unsupported by the data. Another problem with the current WHO schema is the difficulty for strictly applying the morphologic criteria for diagnosis for the different histotypes as currently defined.1 The various subtypes in the WHO classification have introduced a level of complexity for the classification of thymoma that is unnecessary and unjustified. A point in hand is the WHO category of type AB thymoma. The concept of this tumour has suffered a transmutation in the new version of the WHO classification that, although subtle, has significantly changed its definition from that in the original proposal. In the original WHO proposal9 it was stated: ‘‘There are 2 major types of thymoma depending on
lymphocyte-rich, lymphoepithelial, and epithelial-rich thymoma of Bernatz and to ‘‘cortical’’ thymoma in the ‘‘histogenetic’’ classification). The B-type thymomas were further subdivided into B1, B2 and B3 based on ‘‘the proportional increase (in relation to the lymphocytes) and emergence of atypia of the neoplastic epithelial cells.’’.9 An AB category was introduced for tumours that were said to show admixtures of these two basic types. Tumours with overt cytologic atypia were termed thymoma type C. No scientific rationale or underlying biologic principle was postulated or offered to support this proposed nomenclature. In fact, the authors stated: ‘‘the terminology chosen here is a non-committal one based on a combination of letters and numbers. It is not proposed as a new classification, but mainly to facilitate comparisons among the many terms and classification schemes that have been offered over the years’’ (italics ours).9 In essence, the WHO schema was essentially a reiteration of the traditional Bernatz et al. classification2 except under a different terminology, and with the addition of a mixed spindle/round cell category (Table 1). A new edition of the WHO classification of thymoma was published in 2004, and is the one currently in use and accepted as the standard WHO classification.1 The new proposal is essentially a reiteration of the original schema, with some minor modifications. The original combination of letters and numbers has been retained in the latest WHO classification, except that ‘‘type C’’ has been changed to ‘‘thymic carcinoma’’. The new proposal (which is no longer authored by Dr. Rosai), however, has introduced some significant changes in their definitions and added new categories for some rare types of thymoma. As with the original proposal, a well-defined biological underlying principle is not articulated; however, the implication throughout the text is that this classification is based on the histogenetic principles of the previous Kirschner and Muller-Hermelink proposal, despite the fact that the authors state: ‘‘available data do not allow us to unequivocally assign thymic tumors to defined functional and anatomical compartments of the normal thymus’’.1 Yet, under the proposed histogenesis for the various types of thymoma, the postulates of the ‘‘histogenetic’’ proposal are applied.
‘‘Simple to understand’’ The virtues of the new nomenclature proposed by the WHO for the classification of thymomas have been both attacked and
Comparison of ‘‘traditional’’ Bernatz et al. classification of thymoma with WHO classification Bernatz et al. classification (1961)
WHO classification (1999)
Spindle cell thymoma Spindle cell thymoma with abundant lymphocytes Lymphocyte-rich thymoma Mixed lymphoepithelial thymoma Epithelial-rich thymoma Thymic carcinoma
WHO type A WHO type AB WHO WHO WHO WHO
type type type type
B1 B2 B3 C
Table 1
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whether the epithelial cells are spindle/oval (type A) or plump, epithelioid (type B). Tumors containing these two morphologies are designated as AB’’. The new version of the WHO classification, however, states: ‘‘thymomas combining type A with B1-like or (rarely) B2-like features are designated type AB’’; and later on in the text they define type AB thymoma as ‘‘.an organotypical thymic epithelial neoplasm composed of a mixture of lymphocyte-poor type A component and a more lymphocyte-rich type B-like component’’ (italics ours).1 In other words, type AB is no longer made up of an admixture of type A and B, but of type A and B-like areas. The type ‘‘B-like’’ areas are designated as such solely on the basis of the abundance of lymphocytes, but the epithelial cells are essentially the same as those in type A. What is in essence being described here is a lymphocyte-rich spindle cell thymoma (or lymphocyte-rich type A thymoma) (Figure 3). This is far removed from the original concept of a tumour
composed of type A plus type B elements. The AB category in the WHO is thus superfluous and could easily be incorporated as a morphologic variant of type A rather than as some biologically distinct and separate tumour type. It is no wonder that in most studies type A and AB always seem to display similar clinical features and biologic behaviour. Along similar lines, the categories of B1eB3 represent a continuous spectrum of nuclear sizes, shapes and chromaticity, making strict separation between them in an adequately sampled specimen from a completely resected tumour an exercise in frustration (see ‘‘reproducibility’’ ahead). Another significant deviation from the original concept introduced by Dr. Rosai in the initial WHO proposal was also incorporated into the latest WHO schema. In the original WHO proposal, type B thymoma was subdivided into B1eB3 based on the ‘‘proportional increase (in relation to the lymphocytes) and emergence of atypia of the neoplastic epithelial cells.’’.9 In other words, type B1 was characterized by a higher number of lymphocytes and fewer epithelial cells, with the epithelial cells being devoid of cytologic atypia, and at the other extreme, B3 thymoma was characterized by the least number of lymphocytes and a predominance of the epithelial cells showing increased cytologic atypia. The current WHO definition, however, states that in B3 thymoma ‘‘the tumor cells are polygonal, medium sized, and the round or elongated nuclei are often folded or grooved and characteristically smaller with less prominent nucleoli than in B2 thymoma’’ (italics ours).1 These contradictory definitions are not only contrary to these authors’ experience, but also contribute to make the current WHO classification more difficult to understand and apply in clinical practice.
Reproducibility Reproducibility is an important requirement for the successful application of any histopathologic classification system in daily practice. A classification that is only understood by its proponents or by only a few experts will not be of much practical value to the majority of practicing pathologists. The reproducibility of the WHO schema has been consistently challenged by several groups. In a multi-centre study by Rieker et al. 12 involving 218 cases reviewed by two pathologists, significant differences in interobserver agreement were noted using the WHO classification. Applying Kappa statistics, where values >0.8 indicate good agreement and values <0.4 poor agreement, interobserver agreement using the Bernatz et al. classification for this group of tumours was 0.94 and for the WHO 0.87. However, interobserver agreement within the B subgroups using the WHO classification was considerably lower (0.49). This prompted the authors to collapse the six WHO categories into three groups by merging A, AB, B1 and B2 into a single group, and having B3 and C as two separate groups. This yielded an interobserver agreement of 0.95. The authors therefore suggested that simplifying the WHO classification into three subgroups would result in enhanced interobserver agreement as well as increase the prognostic significance for the various groups.12 Several studies have demonstrated that the WHO subtypes A through B2, when in similar stage, share the same biologic behaviour and prognosis. A significant jump in biologic aggressiveness occurs with WHO type B3, and a further increase in aggressiveness ensues with type C (thymic carcinoma). Thus,
WHO type AB thymoma. a Scanning magnification showing areas predominantly composed of fascicles of spindle cells devoid of lymphocytes admixed with areas containing abundant lymphocytes; b higher magnification of ‘‘type A’’ area showing spindle thymic epithelial cells devoid of lymphocytes; c higher magnification of ‘‘type B-like’’ area showing identical spindle cells as in the previous field, admixed with more abundant lymphocytes. Figure 3
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dividing thymic epithelial neoplasms into three groups (Group I: WHO type A, AB, B1 and B2; Group II: WHO type B3; and Group III: WHO type C/thymic carcinoma) will be highly predictive of survival.12,17,18 A recent meta-analysis encompassing 15 studies using the WHO classification published between 2002 and 2005 and involving 2192 thymoma patients showed that only three WHO categories were associated with significant survival differences.19 The same study also highlighted the tremendous heterogeneity observed in the cohorts of patients from the various studies. For example, there was considerable variability with regard to the proportion of thymoma subtypes in the various studies. In fact, studies published from the same country, such as Japan, demonstrated considerable variability in the proportion of the different thymoma subtypes among different studies. This variability within this similar ethnic group suggests that different pathologists may be using the diagnostic criteria of the WHO classification differently and that the various WHO subtypes are being interpreted by different pathologists in an inconsistent manner. Two additional recent studies have also addressed the issue of the difficulties with reproducibility for the WHO classification of thymoma. One involved a study of 97 tumours by a panel of 17 expert thoracic pathologists from the UK and the Netherlands. The results of their study were subjected to statistical analysis using Kappa statistics. The overall level of agreement was 0.45; however, when the WHO categories were collapsed into only two groups (Group I: WHO type A, AB, B1 and B2; Group II: WHO type B3 and C), the level of agreement increased to 0.62.20 Another study from Italy on 85 thymoma patients using the WHO schema found an interobserver agreement of 0.57.21 When they classified the same tumours according to the simplified three-tiered system proposed by Suster and Moran,22 the interobserver agreement increased to 0.97.21 It is clear from these observations that the complexity of the current WHO subtypes creates problems for reproducibility and interobserver agreement.
particularly those showing organotypical features of differentiation (i.e., well-differentiated thymic epithelial neoplasms), the clinical behaviour will be a reflection of their stage at the time of diagnosis and status of resectability (i.e., the higher the stage, the worse the prognosis, independent of the histologic subtype). As previously mentioned, the current WHO book has shown a significant departure from the original proposal by Dr. Rosai in 1999 by claiming that histology is a significant independent prognostic factor and that the various WHO subtypes directly correlate with patient outcome in a incremental, stepwise fashion.1 Several studies have been published that purport to validate this claim.17,25e28 The majority of them, however, have shown no statistically significant differences between several of the subtypes despite their claims to the contrary. The most telling evidence for this is the previously mentioned meta-analysis of the 15 largest studies using the WHO classification published in the recent literature which showed that there were no statistical differences in survival rates between WHO thymomas of type A, AB, and B1.19 Other studies, such as that by Rieker et al. 12 have shown that survival curves for thymoma type A, AB, B1 and B2 are virtually super imposable. The notion that the majority of organotypical thymomas (A, AB, B1, B2) are low-grade malignant neoplasms whose prognosis will depend on their staging rather than the histology has also been supported by recent genetic studies which have shown that WHO type B3 and C are strongly related by their chromosomal imbalances.29e32 Using comparative genomic hybridization, thymomas have been demonstrated to fall into two clusters. The first cluster is characterized by gains of the chromosomal arm 1q as well as losses on 6q and 16q in type B3 and C thymomas. The second cluster is composed of thymoma type A, AB, B1 and B2, which do not exhibit any of these chromosomal abnormalities.30 Obviously, exceptions can occur and occasional B3 and C thymomas may lack chromosomal losses in 6q and 16q and these may be occasionally observed in some of the other types, but the bulk of the evidence clearly supports the concept that B3 and C thymoma types represent a biologically different group of thymic neoplasms than the better differentiated types of thymoma.
Clinical correlation and prognostication One of the key attributes of any tumour classification system is to have the ability to show a good correlation between the various categories and patient outcome. Correlating clinical behaviour and prognosis with the histopathologic features of thymomas has been an area of controversy for decades. We will not go into detail here regarding this controversy, but suffice it to say that the bulk of the evidence in the published literature has supported clinical staging and status of resectability as the most important predictive factor for the prognosis of these tumours.19,21,23 Histology appears to be of importance as an independent prognostic factor only when associated with cytologic atypia of the proliferating thymic epithelial cells. We have been postulating for years this principle and pointing out that a jump in biologic aggressiveness occurs in thymoma when cytologic atypia supervenes.22,24 It is our belief that tumours showing moderate cytologic atypia (such as WHO type B3 thymoma and some forms of low-grade thymic carcinoma, such as well-differentiated squamous or mucoepidermoid carcinoma) and severe cytologic atypia (such as other morphologic types of thymic carcinoma) should be expected to behave more aggressively independent of the stage. But for all other thymic epithelial neoplasms,
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Summary We have argued in the past for the adoption of a more simplified approach to the classification of thymic epithelial neoplasms.22,33e35 In 1999, we presented a novel proposal for the histologic classification of thymomas that was based on the timehonoured biological principle of tumour differentiation.22 As with any other epithelial neoplasm, thymoma can be classified histologically into three simple categories based on their degree of organotypical differentiation. This three-tiered system (well, moderately and poorly differentiated thymic epithelial neoplasms) has traditionally worked well in other organ systems, and the recent literature seems to support our contention that it can work equally well for thymic epithelial neoplasms.15,21,23 We have no quarrel with the WHO’s choice of terminology or the proposed subtypes, which we believe simply represent major morphologic archetypes for thymic tumours. Our objections to the current WHO schema thus do not lie in the categories per se, or even in the choice of terminology employed. Whether they are designated using a combination of letters and numbers, using
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8 Kirschner T, Muller-Hermelink HK. New approaches to the diagnosis of thymic epithelial tumors. Prog Surg Pathol 1989; 10: 167e89. 9 Rosai J. Histological typing of tumors of the thymus. In: World Health Organization international histological classification of tumors. 2nd edn. Berlin: Springer-Verlag, 1999. 10 Chen G, Marx A, Wen-Hu C, et al. New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 2002; 95: 420e9. 11 Chalabreysse L, Roy P, Cordier J-F, Loire R, Gamondes J-P, ThivoletBejui F. Correlation of the WHO schema for the classification of thymic epithelial neoplasms with prognosis. A retrospective study of 90 tumors. Am J Surg Pathol 2002; 26: 1605e11. 12 Rieker RJ, Hoegel J, Morresi-Hauf A, et al. Histologic classification of thymic epithelial tumors: comparison of established classification schemes. Int J Cancer 2002; 98: 900e6. 13 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: 624e32. 14 Pan C-C, Wu H-P, Yang C-F, Chen Y-K, Chieng H. The clinicopathologic correlation of epithelial subtyping in thymoma: a study of 112 consecutive cases. Hum Pathol 1994; 25: 893e9. 15 Regnard J-F, 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: 376e84. 16 Bergh NP, Gatzinsky P, Larson S, Lundin P, Ridell B. Tumors of the thymus and thymic region: I. Clinicopathological studies on thymomas. Ann Thorac Surg 1978; 25: 91e8. 17 Kim DJ, Yang WI, Choi SS, Kim KD, Chung KY. Prognostic and clinical relevance of the World Health Organization schema for the classification of thymic epithelial tumors: a clinicopathologic study of 18 patients and literature review. Chest 2005; 127: 755e61. 18 Sonobe S, Miyamoto H, Izumi H, et al. Clinical usefulness of the WHO histological classification of thymoma. Ann Thorac Cardiovasc Surg 2005; 11: 367e73. 19 Marchevsky AM, Gupta R, McKenna RJ, et al. Evidence-based pathology and the pathologic evaluation of thymomas. The World Health Organization classification can be simplified into only 3 categories other than thymic carcinoma. Cancer 2008; 112: 2780e8. 20 Verghese ET, den Bakker MA, Campbell A, et al. Interobserver variation in the classification of thymic tumors e a multicentre study using the WHO classification system. Histopathology 2008; 53: 218e23. 21 Rossi G, Constantini M, Tagliavini E, Barbieri F, Migdali M, Casalli C. Thymoma classification: does it matter? Histopathology 2008; 53: 483e4. 22 Suster S, Moran CA. Thymoma, atypical thymoma and thymic carcinoma. A novel conceptual approach to the classification of neoplasms of thymic epithelium. Am J Clin Pathol 1999; 111: 826e33. 23 Addis BJ, den Bakker MA. Classifying thymomas. Histopathology 2008; 52: 759e66. 24 Suster S, Moran CA. Primary thymic epithelial neoplasms. Spectrum of differentiation and histologic features. Semin Diagn Pathol 1999; 16: 2e17. 25 Nakagawa K, Asamura H, Matsuno Y, et al. Thymoma: a clinicopathologic study based on the new World Health Organization classification. J Thorac Cardiovasc Surg 2006; 126: 1134e40. 26 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: 992e8.
descriptive morphologic terms based on cell shape and proportion of lymphocytes or by eponymic or other designations is irrelevant. It is how these various categories are approached and interpreted that really matters. Much talk has been made regarding molecular and genetic characterization of thymic tumours. Yet, we have seen very little progress in the genetic characterization of these tumours as their rarity precludes their turning into a major focus of funded research and it may still take years before any significant breakthroughs are obtained. In the meanwhile, patients continue to develop thymomas and, for those unfortunate enough to be afflicted by this disease, how the tumour is categorized and understood by their physicians in the ‘‘here and now’’ is of critical importance. Our appeal has been for the development of a histologic classification that will serve the best interest of the patient by providing a simple, reproducible approach that can be reliably and confidently applied by pathologists across the world without the need for resorting to a few select specialists (except for the occasional rare presentation or unusual variant), and that will provide sensible and reproducible information to our clinical colleagues to make an informed decision regarding therapeutic options. In the past we have proposed that these tumours be approached in the same manner as some of the paediatric tumours by stratifying them into groups with favourable and unfavourable prognosis.36 This would render bickering over terminology and classifications a moot point. However, so far only one group has taken the lead in exploring this option.37 Ten years have elapsed since the introduction of the WHO terminology by Dr. Rosai.9 Much information has been gathered since then, some of it has been conflicting and contradictory but, at the end of the day, certain trends have evidently begun to emerge.19 The time may be ripe to revisit some of these concepts and issues and come up with a proposal that adequately addresses some of the shortcomings and inconsistencies in the current WHO terminology. In the end, all classifications are, by their very nature ‘‘provisional’’, and history has demonstrated that revisions and changes to any classification are simply a part of life. Carpe diem! A
REFERENCES 1 Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. World Health Organization classification of tumors. Pathology and genetics. Tumors of the lung, pleura, thymus and heart. Lyon: IARC Press, 2004. 2 Bernatz PE, Harrison EG, Claggett OT. Thymoma. A clinicopathologic study. J Thorac Cardiovasc Surg 1961; 42: 424e44. 3 Lattes R, Jonas S. Pathological and clinical features in 80 cases of thymoma. Bull N Y Acad Med 1957; 33: 145e7. 4 Bernatz PE, Khonsari S, Harrison Jr EG, Taylor WF. Thymoma: factors influencing prognosis. Surg Clin North Am 1973; 53: 885e92. 5 Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981; 48: 2485e92. 6 Verley JM, Hollmann KH. Thymoma. A comparative clinical study of clinical stages, histologic features, and survival in 200 cases. Cancer 1985; 55: 1074e96. 7 Marino M, Muller-Hermelink HK. Thymoma and thymic carcinoma: relation of thymoma epithelial cells to the cortical and medullary differentiation of the thymus. Virchows Archiv 1985; 407: 119e49.
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27 Kondo K, Yoshizawa K, Tsuyugushi M, et al. WHO histologic classification is prognostic indicator in thymoma. Ann Thorac Surg 2004; 77: 1183e8. 28 Okumura M, Miyoshi S, Fujii Y, et al. Clinical and functional significance of WHO classification of thymic epithelial neoplasms. A study of 146 consecutive tumors. Am J Surg Pathol 2001; 25: 103e10. 29 Inoue M, Starostik P, Zettl A, et al. Correlating genetic aberrations with World Health Organization-defined histology and stage across the spectrum of thymomas. Cancer Res 2003; 63: 3708e15. 30 Penzel B, Hoegel J, Schmitz W, et al. Clusters of chromosomal imbalances in thymic epithelial tumors are associated with the WHO classification and the staging system according to Masaoka. Int J Cancer 2003; 105: 494e8. 31 Zettl A, Strobel P, Wagner K, et al. Recurrent genetic aberrations in thymoma and thymic carcinoma. Am J Pathol 2003; 157: 257e66. 32 Zhou R, Zettl A, Strobel P, et al. Thymic epithelial tumors can develop along two different pathogenetic pathways. Am J Pathol 2001; 159: 1853e60. 33 Suster S, Moran CA. Thymoma classification: current status and future trends. Am J Clin Pathol 2006; 125: 542e54. 34 Suster S, Moran CA. Problem areas and inconsistencies in the WHO classification of thymoma. Semin Diagn Pathol 2005; 22: 188e97. 35 Suster S, Moran CA. Classification of thymoma: the WHO and beyond. Hematol Oncol Clin North Am 2008; 22: 381e92.
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36 Suster S, Moran CA. The thymus. In: Weidner N, Cote RJ, Suster S, Weiss LM, eds. Modern surgical pathology. 2nd edn. Philadelphia: Saunders Elsevier, 2009: 454e516. 37 D’Angelillo RM, Trodella L, Ramella S, et al. Novel prognostic groups in thymic epithelial tumors: assessment of risk and therapeutic strategy selection. Int J Radiat Oncol Biol Phys 2008; 71: 420e7.
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Reproducibility of WHO classification of thymoma is low, particularly for the B-subtypes Heterogeneity of thymic epithelial neoplasms makes it very difficult to reliably apply the morphologic criteria of the WHO classification The revised histologic criteria in the latest (2004) WHO classification conflict with many of the tenets in the original WHO (1999) proposal Clinical staging continues to be the most important prognostic parameter for thymic epithelial neoplasms Immunohistochemistry and molecular pathology still play a very limited role for the diagnosis and prognostication of these tumours
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Problems in the classification of thymoma
letters and numbers to identify various histologic types of thymoma.1 This WHO classification of tumours of the thymus has been widely embraced by pathologists worldwide and has received the enthusiastic support of the establishment. Yet, some nagging issues continue to linger which begs the question: is this classification ideal and is there still room for improvement? In this review, we will briefly examine some of the controversial issues surrounding the current WHO classification of tumours of the thymus, including issues of reproducibility, interobserver variability, clinical significance of the various subtypes, and the biological rationale that supports the current classification scheme. The purpose is not to be critical simply for the sake of argument, but to offer constructive criticism and frame the issue in its proper perspective, i.e., what is best for the patient, so that appropriate adjustments and improvements can be made.
Saul Suster Cesar A Moran
Abstract The histologic classification of thymoma has posed difficulties for pathologists for many years and continues to be a focus of controversy in the speciality today. In recent years, the World Health Organization (WHO) has assembled a panel of experts with the purpose of devising a histologic classification system of thymoma that will be widely adopted for common use by pathologists and clinicians throughout the world. This objective has been largely accomplished with the introduction of the WHO histologic classification of tumours of the thymus. Despite the widespread acceptance of this classification, however, several controversial issues have remained unaddressed that still require attention. Herein we review briefly some of the issues that pose a challenge and require improvement in our current classification of thymomas, including issues related to ease of applicability of this classification and interobserver reproducibility in daily practice, the lack of a unifying, underlying biologic principle, the limitations for the stratification of patients for clinical management and the accuracy of some of the assumptions behind the definitions for some of the different proposed histologic types.
Biological basis of classification Setting aside classification schemes for thymoma that pre-date the one proposed by Bernatz et al. 2 in 1961from the Mayo Clinic, all subsequent modern schemes have been based on morphology and have not managed to provide a clear advantage over any of its competitors. The Bernatz et al. 2 schema, which was based on an earlier proposal by Dr. Rafaelle Lattes from Columbia University in New York,3 relied on the shape of the proliferating epithelial cells and the relative proportion of intratumoural lymphocytes for separating these tumours into four categories. This was an admittedly purely morphological classification whose main value resided in identifying the main prototypical histologic variants of thymoma for proper identification and to avoid misdiagnosing them for other conditions. However, it was acknowledged by the authors early on that the various histologic types did not correlate well with prognosis, and that the staging of the tumours constituted the most reliable tool for assessing their clinical behaviour.4 Subsequent thymoma classification proposals from Japan and France5,6 were also based on morphology and also lacked a unifying biologic basis. An apparent major breakthrough occurred in 1985 with the introduction of a new classification approach for thymoma introduced by Drs. Marino and MullerHermelink.7 Succinctly stated, their proposal claimed that thymomas were either derived from the cortex or the medulla of the thymus, with allowances for the existence of hybrid or ‘‘mixed’’ tumours showing an admixture of the two. Thus, thymomas were designated as of cortical, medullary or mixed type. This was the first time that a plausible histogenetic basis was ascribed to thymoma, and the proposal was dubbed the ‘‘histogenetic’’ classification. Predictably, this novel proposal was enthusiastically received by pathologists worldwide and gained wide acceptance and popularity. Over time, however, the complexity of the situation and the limitations for applying this schema became increasingly apparent to the authors and they had to admit that their proposed categories were not sufficient to explain the entire spectrum of observed thymic tumours. Thus, in 1989, a revised classification was presented by Kirschner and Muller-Hermelink8 that added two new categories to the previous schema; predominantly cortical (or ‘‘organoid’’) thymoma and ‘‘well-differentiated thymic
Keywords classification; thymic carcinoma; thymic epithelial neoplasm; thymoma
Introduction The classification of thymoma has been a controversial issue for many years. A large number of classification schemes have been presented over the years with varying rates of acceptance and success for applying them to clinical practice. Although all of the proposed schemas managed to accrue a loyal following and were indeed helpful as a guide for pathologists, none of them really managed to fulfil all of the intended requirements that a histopathologic classification of tumours should provide. For a histologic classification of any family of tumours to fulfil its role in the practice of medicine, it must be simple to understand, reproducible, and convey clinically relevant and significant information that rests on a solid biological basis. The latter characteristic, in particular, has consistently plagued and eluded classification systems of thymoma. In recent years, a panel of experts appointed by the WHO has devised a classification system that is based on a combination of
Saul Suster MD is Professor and Chairman, at the Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. Conflicts of interest: none. Cesar A Moran MD is Professor of Pathology at the University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. Conflicts of interest: none.
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carcinoma’’. Despite the great success and acceptance of the ‘‘histogenetic’’ classification, the biological underpinnings of this proposal were questioned by some. From a purely morphologic perspective, the morphotypes assigned to the different histogenetic designations appeared to be somewhat arbitrary and conflicted with the histologic appearance of the tumours. For example the tumours designated as ‘‘medullary’’ were those characterized by a predominant spindle cell population with paucity of lymphocytes. In traditional morphology, descriptive terms that allude to normal anatomic structures are expected to relate to processes that closely resemble histologically such normal structures. In the case of ‘‘medullary’’ thymoma, the dense spindle cell proliferation ascribed to such tumours did not even remotely resemble the normal medulla of the thymus (Figure 1). In fact, it was pointed out by Dr. Rosai in the initial WHO monograph9 that, if anything, the spindle cells in ‘‘medullary’’ thymoma most closely resembled the ‘‘effete’’, involuted thymic epithelial cells observed in thymic remnants of adults rather than the normal thymus medulla. The ‘‘mixed’’ tumours in the ‘‘histogenetic’’ classification also comprised a heterogeneous group that was difficult to define. In fact, the tumour designated by the authors as ‘‘predominantly cortical’’ was the only morphologic type of thymoma in their schema that could properly be categorized as ‘‘mixed’’ from a purely histogenetic point of view because it is the only type of thymoma that is truly composed of an admixture of well-developed and recognizable cortical and medullary areas that faithfully recapitulate these structures in the normal functional thymus (Figure 2).8 Further evidence to support the validity of the ‘‘histogenetic’’ proposal was sought from the immunohistochemical characterization of the cell phenotype in these tumours. Various attempts at analysing the subtypes of these tumours for various putative specific markers were made with little success. In fact, it was the authors of the ‘‘histogenetic’’ classification themselves who, with impeccable scientific integrity, acknowledged that .‘‘Using specific
Comparison of ‘‘predominantly cortical’’ thymoma with normal thymus: a predominantly cortical thymoma showing well-defined cortical zones admixed with well-defined medullary areas containing Hassall’s corpuscles; b normal mature functional thymus in a 10-year-old boy showing close resemblance to ‘‘a’’, with a welldeveloped cortex and medulla. Figure 2
monoclonal antibodies, specific immunophenotypes of the different histological tumor types cannot be defined. Therefore, presence or absence of reactivity with one of these monoclonal antibodies does not allow clear immunohistochemical differentiation between the different tumor types. Furthermore, the immunophenotype of the epithelial neoplastic cells cannot be strictly correlated to the immunophenotype of different epithelial cells in the thymus’’.8 Because of the confusion that still lingered around the histologic classification of thymoma, when the World Health Organization (WHO) was preparing to launch its second series of books devoted to the histologic classification of tumours, they invited Juan Rosai to assemble an international panel of experts to devise a definitive histologic classification of thymoma. The results of the panel’s deliberations led them to the realization that none of the existing classifications truly fulfilled all the requirements to enjoy universal acceptance. This led to the proposal for devising a schema that was based on a combination of letters and numbers that would allow authors using different terminologies to find a common designation for some of the most common morphologic types of thymoma. This new proposal became the first WHO classification of thymic tumours which was formally published in 1999.9 Once again, this new proposal by the WHO lacked a unifying scientific explanation for the various histologic types and was also based on morphology, relying on the same principles as the previous Bernatz et al. classification2 for separating thymomas based on their cell shape (round/plump/epithelioid vs. spindle/oval) and on their relative proportion of intratumoural lymphocytes. Thus, thymomas were said to be of two basic types, those predominantly composed of spindle/oval cells were designated as type A (equivalent to the spindle cell thymoma of Bernatz and to ‘‘medullary’’ thymoma of the ‘‘histogenetic’’ classification), and those composed of plump/ epithelioid cells were designated as type B (equivalent to
Comparison of ‘‘medullary’’ thymoma with the normal medulla: a ‘‘medullary’’ thymoma predominantly composed of a bland spindle cell population; b normal medulla in a functionally mature thymus. Figure 1
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staunchly defended over the past few years. Objections have been expressed to the effect that using letters and numbers goes against the established precedent of designating tumours in a more informative way using terms that will intuitively guide our clinical colleagues to an understanding of the nature of the process. Such objections have been countered by the anecdotal information provided by the WHO proponents that clinicians and surgeons ‘‘love’’ this terminology and are very happy with it. For an inquisitive mind, the use of various letters and numbers in a classification implies the existence of a strict rationale behind it; i.e., if there is a type B1eB2eB3, why aren’t there corresponding type A1eA2eA3? If there is a type AB, why isn’t there a type AC and BC? In fact, given the absence of an underlying theme or biologic explanation for the letters and numbers, wouldn’t it be simpler and more straightforward to simply designate these tumours as type 1 through 6 or A through F? What is the rationale and where is the need for the added complication behind the various letters and numbers? The justification that has been put forth by the WHO is that the different subtypes show a good correlation with the clinical behaviour of the lesions. Although a clinical correlation with the biologic behaviour of the tumours was not part of the original proposal presented by Dr. Rosai in 1999,9 the current WHO book claims that thymomas of type A and AB are benign, type B1 is a low-grade malignancy, type B2 is characterized by a ‘‘greater degree’’ of malignancy, and type B3 (in advanced stages) is equivalent to thymic carcinoma.1 This opinion is based on a single study by Prof. Muller-Hermelink and colleagues in 200 patients from China.10 The results of their study illustrated in the WHO book show a survival curve with a nice stepwise progression for these tumours from thymoma type A through B3. The problem is that this data has not been validated by other studies. A study by Chalabraysse et al. from France11 published the same year applying the WHO classification showed a worse prognosis for type A and AB tumours than for the type B tumours. Another multi-centre study from Germany published the same year showed essentially overlapping survival curves for patients with type A and B2 tumours.12 Another study from Japan, also published the same year, showed a better survival for patients with B1 thymoma than for type AB thymoma.13 Moreover, the contention by the WHO that type A thymoma is benign is in stark conflict with a large body of literature that has documented aggressive behaviour and tumour deaths in patients with spindle cell thymoma (WHO type A).2e6,11,12,14e16 The justification for using the combination of letters and numbers proposed by the WHO to designate these tumours based on their progressive correlation with an aggressive patient outcome is therefore unsupported by the data. Another problem with the current WHO schema is the difficulty for strictly applying the morphologic criteria for diagnosis for the different histotypes as currently defined.1 The various subtypes in the WHO classification have introduced a level of complexity for the classification of thymoma that is unnecessary and unjustified. A point in hand is the WHO category of type AB thymoma. The concept of this tumour has suffered a transmutation in the new version of the WHO classification that, although subtle, has significantly changed its definition from that in the original proposal. In the original WHO proposal9 it was stated: ‘‘There are 2 major types of thymoma depending on
lymphocyte-rich, lymphoepithelial, and epithelial-rich thymoma of Bernatz and to ‘‘cortical’’ thymoma in the ‘‘histogenetic’’ classification). The B-type thymomas were further subdivided into B1, B2 and B3 based on ‘‘the proportional increase (in relation to the lymphocytes) and emergence of atypia of the neoplastic epithelial cells.’’.9 An AB category was introduced for tumours that were said to show admixtures of these two basic types. Tumours with overt cytologic atypia were termed thymoma type C. No scientific rationale or underlying biologic principle was postulated or offered to support this proposed nomenclature. In fact, the authors stated: ‘‘the terminology chosen here is a non-committal one based on a combination of letters and numbers. It is not proposed as a new classification, but mainly to facilitate comparisons among the many terms and classification schemes that have been offered over the years’’ (italics ours).9 In essence, the WHO schema was essentially a reiteration of the traditional Bernatz et al. classification2 except under a different terminology, and with the addition of a mixed spindle/round cell category (Table 1). A new edition of the WHO classification of thymoma was published in 2004, and is the one currently in use and accepted as the standard WHO classification.1 The new proposal is essentially a reiteration of the original schema, with some minor modifications. The original combination of letters and numbers has been retained in the latest WHO classification, except that ‘‘type C’’ has been changed to ‘‘thymic carcinoma’’. The new proposal (which is no longer authored by Dr. Rosai), however, has introduced some significant changes in their definitions and added new categories for some rare types of thymoma. As with the original proposal, a well-defined biological underlying principle is not articulated; however, the implication throughout the text is that this classification is based on the histogenetic principles of the previous Kirschner and Muller-Hermelink proposal, despite the fact that the authors state: ‘‘available data do not allow us to unequivocally assign thymic tumors to defined functional and anatomical compartments of the normal thymus’’.1 Yet, under the proposed histogenesis for the various types of thymoma, the postulates of the ‘‘histogenetic’’ proposal are applied.
‘‘Simple to understand’’ The virtues of the new nomenclature proposed by the WHO for the classification of thymomas have been both attacked and
Comparison of ‘‘traditional’’ Bernatz et al. classification of thymoma with WHO classification Bernatz et al. classification (1961)
WHO classification (1999)
Spindle cell thymoma Spindle cell thymoma with abundant lymphocytes Lymphocyte-rich thymoma Mixed lymphoepithelial thymoma Epithelial-rich thymoma Thymic carcinoma
WHO type A WHO type AB WHO WHO WHO WHO
type type type type
B1 B2 B3 C
Table 1
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whether the epithelial cells are spindle/oval (type A) or plump, epithelioid (type B). Tumors containing these two morphologies are designated as AB’’. The new version of the WHO classification, however, states: ‘‘thymomas combining type A with B1-like or (rarely) B2-like features are designated type AB’’; and later on in the text they define type AB thymoma as ‘‘.an organotypical thymic epithelial neoplasm composed of a mixture of lymphocyte-poor type A component and a more lymphocyte-rich type B-like component’’ (italics ours).1 In other words, type AB is no longer made up of an admixture of type A and B, but of type A and B-like areas. The type ‘‘B-like’’ areas are designated as such solely on the basis of the abundance of lymphocytes, but the epithelial cells are essentially the same as those in type A. What is in essence being described here is a lymphocyte-rich spindle cell thymoma (or lymphocyte-rich type A thymoma) (Figure 3). This is far removed from the original concept of a tumour
composed of type A plus type B elements. The AB category in the WHO is thus superfluous and could easily be incorporated as a morphologic variant of type A rather than as some biologically distinct and separate tumour type. It is no wonder that in most studies type A and AB always seem to display similar clinical features and biologic behaviour. Along similar lines, the categories of B1eB3 represent a continuous spectrum of nuclear sizes, shapes and chromaticity, making strict separation between them in an adequately sampled specimen from a completely resected tumour an exercise in frustration (see ‘‘reproducibility’’ ahead). Another significant deviation from the original concept introduced by Dr. Rosai in the initial WHO proposal was also incorporated into the latest WHO schema. In the original WHO proposal, type B thymoma was subdivided into B1eB3 based on the ‘‘proportional increase (in relation to the lymphocytes) and emergence of atypia of the neoplastic epithelial cells.’’.9 In other words, type B1 was characterized by a higher number of lymphocytes and fewer epithelial cells, with the epithelial cells being devoid of cytologic atypia, and at the other extreme, B3 thymoma was characterized by the least number of lymphocytes and a predominance of the epithelial cells showing increased cytologic atypia. The current WHO definition, however, states that in B3 thymoma ‘‘the tumor cells are polygonal, medium sized, and the round or elongated nuclei are often folded or grooved and characteristically smaller with less prominent nucleoli than in B2 thymoma’’ (italics ours).1 These contradictory definitions are not only contrary to these authors’ experience, but also contribute to make the current WHO classification more difficult to understand and apply in clinical practice.
Reproducibility Reproducibility is an important requirement for the successful application of any histopathologic classification system in daily practice. A classification that is only understood by its proponents or by only a few experts will not be of much practical value to the majority of practicing pathologists. The reproducibility of the WHO schema has been consistently challenged by several groups. In a multi-centre study by Rieker et al. 12 involving 218 cases reviewed by two pathologists, significant differences in interobserver agreement were noted using the WHO classification. Applying Kappa statistics, where values >0.8 indicate good agreement and values <0.4 poor agreement, interobserver agreement using the Bernatz et al. classification for this group of tumours was 0.94 and for the WHO 0.87. However, interobserver agreement within the B subgroups using the WHO classification was considerably lower (0.49). This prompted the authors to collapse the six WHO categories into three groups by merging A, AB, B1 and B2 into a single group, and having B3 and C as two separate groups. This yielded an interobserver agreement of 0.95. The authors therefore suggested that simplifying the WHO classification into three subgroups would result in enhanced interobserver agreement as well as increase the prognostic significance for the various groups.12 Several studies have demonstrated that the WHO subtypes A through B2, when in similar stage, share the same biologic behaviour and prognosis. A significant jump in biologic aggressiveness occurs with WHO type B3, and a further increase in aggressiveness ensues with type C (thymic carcinoma). Thus,
WHO type AB thymoma. a Scanning magnification showing areas predominantly composed of fascicles of spindle cells devoid of lymphocytes admixed with areas containing abundant lymphocytes; b higher magnification of ‘‘type A’’ area showing spindle thymic epithelial cells devoid of lymphocytes; c higher magnification of ‘‘type B-like’’ area showing identical spindle cells as in the previous field, admixed with more abundant lymphocytes. Figure 3
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dividing thymic epithelial neoplasms into three groups (Group I: WHO type A, AB, B1 and B2; Group II: WHO type B3; and Group III: WHO type C/thymic carcinoma) will be highly predictive of survival.12,17,18 A recent meta-analysis encompassing 15 studies using the WHO classification published between 2002 and 2005 and involving 2192 thymoma patients showed that only three WHO categories were associated with significant survival differences.19 The same study also highlighted the tremendous heterogeneity observed in the cohorts of patients from the various studies. For example, there was considerable variability with regard to the proportion of thymoma subtypes in the various studies. In fact, studies published from the same country, such as Japan, demonstrated considerable variability in the proportion of the different thymoma subtypes among different studies. This variability within this similar ethnic group suggests that different pathologists may be using the diagnostic criteria of the WHO classification differently and that the various WHO subtypes are being interpreted by different pathologists in an inconsistent manner. Two additional recent studies have also addressed the issue of the difficulties with reproducibility for the WHO classification of thymoma. One involved a study of 97 tumours by a panel of 17 expert thoracic pathologists from the UK and the Netherlands. The results of their study were subjected to statistical analysis using Kappa statistics. The overall level of agreement was 0.45; however, when the WHO categories were collapsed into only two groups (Group I: WHO type A, AB, B1 and B2; Group II: WHO type B3 and C), the level of agreement increased to 0.62.20 Another study from Italy on 85 thymoma patients using the WHO schema found an interobserver agreement of 0.57.21 When they classified the same tumours according to the simplified three-tiered system proposed by Suster and Moran,22 the interobserver agreement increased to 0.97.21 It is clear from these observations that the complexity of the current WHO subtypes creates problems for reproducibility and interobserver agreement.
particularly those showing organotypical features of differentiation (i.e., well-differentiated thymic epithelial neoplasms), the clinical behaviour will be a reflection of their stage at the time of diagnosis and status of resectability (i.e., the higher the stage, the worse the prognosis, independent of the histologic subtype). As previously mentioned, the current WHO book has shown a significant departure from the original proposal by Dr. Rosai in 1999 by claiming that histology is a significant independent prognostic factor and that the various WHO subtypes directly correlate with patient outcome in a incremental, stepwise fashion.1 Several studies have been published that purport to validate this claim.17,25e28 The majority of them, however, have shown no statistically significant differences between several of the subtypes despite their claims to the contrary. The most telling evidence for this is the previously mentioned meta-analysis of the 15 largest studies using the WHO classification published in the recent literature which showed that there were no statistical differences in survival rates between WHO thymomas of type A, AB, and B1.19 Other studies, such as that by Rieker et al. 12 have shown that survival curves for thymoma type A, AB, B1 and B2 are virtually super imposable. The notion that the majority of organotypical thymomas (A, AB, B1, B2) are low-grade malignant neoplasms whose prognosis will depend on their staging rather than the histology has also been supported by recent genetic studies which have shown that WHO type B3 and C are strongly related by their chromosomal imbalances.29e32 Using comparative genomic hybridization, thymomas have been demonstrated to fall into two clusters. The first cluster is characterized by gains of the chromosomal arm 1q as well as losses on 6q and 16q in type B3 and C thymomas. The second cluster is composed of thymoma type A, AB, B1 and B2, which do not exhibit any of these chromosomal abnormalities.30 Obviously, exceptions can occur and occasional B3 and C thymomas may lack chromosomal losses in 6q and 16q and these may be occasionally observed in some of the other types, but the bulk of the evidence clearly supports the concept that B3 and C thymoma types represent a biologically different group of thymic neoplasms than the better differentiated types of thymoma.
Clinical correlation and prognostication One of the key attributes of any tumour classification system is to have the ability to show a good correlation between the various categories and patient outcome. Correlating clinical behaviour and prognosis with the histopathologic features of thymomas has been an area of controversy for decades. We will not go into detail here regarding this controversy, but suffice it to say that the bulk of the evidence in the published literature has supported clinical staging and status of resectability as the most important predictive factor for the prognosis of these tumours.19,21,23 Histology appears to be of importance as an independent prognostic factor only when associated with cytologic atypia of the proliferating thymic epithelial cells. We have been postulating for years this principle and pointing out that a jump in biologic aggressiveness occurs in thymoma when cytologic atypia supervenes.22,24 It is our belief that tumours showing moderate cytologic atypia (such as WHO type B3 thymoma and some forms of low-grade thymic carcinoma, such as well-differentiated squamous or mucoepidermoid carcinoma) and severe cytologic atypia (such as other morphologic types of thymic carcinoma) should be expected to behave more aggressively independent of the stage. But for all other thymic epithelial neoplasms,
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Summary We have argued in the past for the adoption of a more simplified approach to the classification of thymic epithelial neoplasms.22,33e35 In 1999, we presented a novel proposal for the histologic classification of thymomas that was based on the timehonoured biological principle of tumour differentiation.22 As with any other epithelial neoplasm, thymoma can be classified histologically into three simple categories based on their degree of organotypical differentiation. This three-tiered system (well, moderately and poorly differentiated thymic epithelial neoplasms) has traditionally worked well in other organ systems, and the recent literature seems to support our contention that it can work equally well for thymic epithelial neoplasms.15,21,23 We have no quarrel with the WHO’s choice of terminology or the proposed subtypes, which we believe simply represent major morphologic archetypes for thymic tumours. Our objections to the current WHO schema thus do not lie in the categories per se, or even in the choice of terminology employed. Whether they are designated using a combination of letters and numbers, using
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8 Kirschner T, Muller-Hermelink HK. New approaches to the diagnosis of thymic epithelial tumors. Prog Surg Pathol 1989; 10: 167e89. 9 Rosai J. Histological typing of tumors of the thymus. In: World Health Organization international histological classification of tumors. 2nd edn. Berlin: Springer-Verlag, 1999. 10 Chen G, Marx A, Wen-Hu C, et al. New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 2002; 95: 420e9. 11 Chalabreysse L, Roy P, Cordier J-F, Loire R, Gamondes J-P, ThivoletBejui F. Correlation of the WHO schema for the classification of thymic epithelial neoplasms with prognosis. A retrospective study of 90 tumors. Am J Surg Pathol 2002; 26: 1605e11. 12 Rieker RJ, Hoegel J, Morresi-Hauf A, et al. Histologic classification of thymic epithelial tumors: comparison of established classification schemes. Int J Cancer 2002; 98: 900e6. 13 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: 624e32. 14 Pan C-C, Wu H-P, Yang C-F, Chen Y-K, Chieng H. The clinicopathologic correlation of epithelial subtyping in thymoma: a study of 112 consecutive cases. Hum Pathol 1994; 25: 893e9. 15 Regnard J-F, 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: 376e84. 16 Bergh NP, Gatzinsky P, Larson S, Lundin P, Ridell B. Tumors of the thymus and thymic region: I. Clinicopathological studies on thymomas. Ann Thorac Surg 1978; 25: 91e8. 17 Kim DJ, Yang WI, Choi SS, Kim KD, Chung KY. Prognostic and clinical relevance of the World Health Organization schema for the classification of thymic epithelial tumors: a clinicopathologic study of 18 patients and literature review. Chest 2005; 127: 755e61. 18 Sonobe S, Miyamoto H, Izumi H, et al. Clinical usefulness of the WHO histological classification of thymoma. Ann Thorac Cardiovasc Surg 2005; 11: 367e73. 19 Marchevsky AM, Gupta R, McKenna RJ, et al. Evidence-based pathology and the pathologic evaluation of thymomas. The World Health Organization classification can be simplified into only 3 categories other than thymic carcinoma. Cancer 2008; 112: 2780e8. 20 Verghese ET, den Bakker MA, Campbell A, et al. Interobserver variation in the classification of thymic tumors e a multicentre study using the WHO classification system. Histopathology 2008; 53: 218e23. 21 Rossi G, Constantini M, Tagliavini E, Barbieri F, Migdali M, Casalli C. Thymoma classification: does it matter? Histopathology 2008; 53: 483e4. 22 Suster S, Moran CA. Thymoma, atypical thymoma and thymic carcinoma. A novel conceptual approach to the classification of neoplasms of thymic epithelium. Am J Clin Pathol 1999; 111: 826e33. 23 Addis BJ, den Bakker MA. Classifying thymomas. Histopathology 2008; 52: 759e66. 24 Suster S, Moran CA. Primary thymic epithelial neoplasms. Spectrum of differentiation and histologic features. Semin Diagn Pathol 1999; 16: 2e17. 25 Nakagawa K, Asamura H, Matsuno Y, et al. Thymoma: a clinicopathologic study based on the new World Health Organization classification. J Thorac Cardiovasc Surg 2006; 126: 1134e40. 26 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: 992e8.
descriptive morphologic terms based on cell shape and proportion of lymphocytes or by eponymic or other designations is irrelevant. It is how these various categories are approached and interpreted that really matters. Much talk has been made regarding molecular and genetic characterization of thymic tumours. Yet, we have seen very little progress in the genetic characterization of these tumours as their rarity precludes their turning into a major focus of funded research and it may still take years before any significant breakthroughs are obtained. In the meanwhile, patients continue to develop thymomas and, for those unfortunate enough to be afflicted by this disease, how the tumour is categorized and understood by their physicians in the ‘‘here and now’’ is of critical importance. Our appeal has been for the development of a histologic classification that will serve the best interest of the patient by providing a simple, reproducible approach that can be reliably and confidently applied by pathologists across the world without the need for resorting to a few select specialists (except for the occasional rare presentation or unusual variant), and that will provide sensible and reproducible information to our clinical colleagues to make an informed decision regarding therapeutic options. In the past we have proposed that these tumours be approached in the same manner as some of the paediatric tumours by stratifying them into groups with favourable and unfavourable prognosis.36 This would render bickering over terminology and classifications a moot point. However, so far only one group has taken the lead in exploring this option.37 Ten years have elapsed since the introduction of the WHO terminology by Dr. Rosai.9 Much information has been gathered since then, some of it has been conflicting and contradictory but, at the end of the day, certain trends have evidently begun to emerge.19 The time may be ripe to revisit some of these concepts and issues and come up with a proposal that adequately addresses some of the shortcomings and inconsistencies in the current WHO terminology. In the end, all classifications are, by their very nature ‘‘provisional’’, and history has demonstrated that revisions and changes to any classification are simply a part of life. Carpe diem! A
REFERENCES 1 Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. World Health Organization classification of tumors. Pathology and genetics. Tumors of the lung, pleura, thymus and heart. Lyon: IARC Press, 2004. 2 Bernatz PE, Harrison EG, Claggett OT. Thymoma. A clinicopathologic study. J Thorac Cardiovasc Surg 1961; 42: 424e44. 3 Lattes R, Jonas S. Pathological and clinical features in 80 cases of thymoma. Bull N Y Acad Med 1957; 33: 145e7. 4 Bernatz PE, Khonsari S, Harrison Jr EG, Taylor WF. Thymoma: factors influencing prognosis. Surg Clin North Am 1973; 53: 885e92. 5 Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981; 48: 2485e92. 6 Verley JM, Hollmann KH. Thymoma. A comparative clinical study of clinical stages, histologic features, and survival in 200 cases. Cancer 1985; 55: 1074e96. 7 Marino M, Muller-Hermelink HK. Thymoma and thymic carcinoma: relation of thymoma epithelial cells to the cortical and medullary differentiation of the thymus. Virchows Archiv 1985; 407: 119e49.
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27 Kondo K, Yoshizawa K, Tsuyugushi M, et al. WHO histologic classification is prognostic indicator in thymoma. Ann Thorac Surg 2004; 77: 1183e8. 28 Okumura M, Miyoshi S, Fujii Y, et al. Clinical and functional significance of WHO classification of thymic epithelial neoplasms. A study of 146 consecutive tumors. Am J Surg Pathol 2001; 25: 103e10. 29 Inoue M, Starostik P, Zettl A, et al. Correlating genetic aberrations with World Health Organization-defined histology and stage across the spectrum of thymomas. Cancer Res 2003; 63: 3708e15. 30 Penzel B, Hoegel J, Schmitz W, et al. Clusters of chromosomal imbalances in thymic epithelial tumors are associated with the WHO classification and the staging system according to Masaoka. Int J Cancer 2003; 105: 494e8. 31 Zettl A, Strobel P, Wagner K, et al. Recurrent genetic aberrations in thymoma and thymic carcinoma. Am J Pathol 2003; 157: 257e66. 32 Zhou R, Zettl A, Strobel P, et al. Thymic epithelial tumors can develop along two different pathogenetic pathways. Am J Pathol 2001; 159: 1853e60. 33 Suster S, Moran CA. Thymoma classification: current status and future trends. Am J Clin Pathol 2006; 125: 542e54. 34 Suster S, Moran CA. Problem areas and inconsistencies in the WHO classification of thymoma. Semin Diagn Pathol 2005; 22: 188e97. 35 Suster S, Moran CA. Classification of thymoma: the WHO and beyond. Hematol Oncol Clin North Am 2008; 22: 381e92.
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36 Suster S, Moran CA. The thymus. In: Weidner N, Cote RJ, Suster S, Weiss LM, eds. Modern surgical pathology. 2nd edn. Philadelphia: Saunders Elsevier, 2009: 454e516. 37 D’Angelillo RM, Trodella L, Ramella S, et al. Novel prognostic groups in thymic epithelial tumors: assessment of risk and therapeutic strategy selection. Int J Radiat Oncol Biol Phys 2008; 71: 420e7.
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Reproducibility of WHO classification of thymoma is low, particularly for the B-subtypes Heterogeneity of thymic epithelial neoplasms makes it very difficult to reliably apply the morphologic criteria of the WHO classification The revised histologic criteria in the latest (2004) WHO classification conflict with many of the tenets in the original WHO (1999) proposal Clinical staging continues to be the most important prognostic parameter for thymic epithelial neoplasms Immunohistochemistry and molecular pathology still play a very limited role for the diagnosis and prognostication of these tumours
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