Classification of Thymic Epithelial Neoplasms Is Still a Challenge to Thoracic Pathologists A Reproducibility Study Using Digital Microscopy Hangjun Wang, MD; Camelia S. Sima, MD, MS; Mary Beth Beasley, MD; Peter Illei, MD; Anjali Saqi, MD; Daisuke Nonaka, MD; Kim R. Geisinger, MD; James Huang, MD; Andre L. Moreira, MD, PhD

 Context.—Thymic epithelial tumors are rare, constituting interpretive challenges for pathologists. Digital imaging can be useful as an educational tool for these rare tumors. Objectives.—To evaluate the diagnostic reproducibility of thymic tumors among thoracic pathologists. Design.—Twenty cases of thymoma or thymic carcinoma were scanned into the Aperio system. The images were sent to pathologists with expertise in thoracic pathology at 6 different centers, who were asked to classify the tumors according to the 2004 World Heath Organization classification and to diagnose invasion. Interobserver agreement was evaluated. After discussion of the first 20 cases, a second set of 10 cases was evaluated. Results.—There was agreement for the diagnosis of thymoma and thymic carcinoma in 70% of cases (n ¼ 14); in the remaining 6 cases, there was disagreement for cases of B3 thymoma (n ¼ 5) and type A thymoma (n ¼ 1) and

thymic carcinoma. The overall j was 0.39. When invasion was evaluated, the overall j was 0.45. In the second round of the study, after discussion of diagnostic criteria, the interobserver agreement for the diagnosis of thymoma versus thymic carcinoma was 0.67 and that for the determination of invasion was 0.57—suggesting interpretative improvement. Conclusion.—The reproducibility of diagnosis of thymic epithelial tumors, using digital imaging, is comparable to that in previous studies using glass slides. Digital imaging is a good tool for remote consultation and for educational purposes. This technology could be used to train pathologists with low-level experience in thymic epithelial tumors and to foster collaborative work in the field. (Arch Pathol Lab Med. 2014;138:658–663; doi: 10.5858/ arpa.2013-0028-OA)

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rare lymphocytes, whereas type B thymomas show polygonal epithelial cells and variable amounts of thymic lymphocytes. Type B thymomas are divided into 3 categories, according to the ratio of lymphocytes to thymic epithelial cells. B1 thymomas are rich in thymic lymphocytes, whereas B3 thymomas are composed predominantly of epithelial cells, with little infiltration by lymphocytes. B2 thymomas contain similar proportions of epithelial cells and lymphocytes. Thymic carcinomas are tumors with overtly cytologic malignant epithelial tumor cells. Thymic carcinomas are also histologically heterogeneous and can be classified as any carcinoma arising from other sites. Thymic squamous cell carcinoma is the most common presentation. Because of the infrequency of these neoplasms and their heterogeneity, rates of interobserver and intraobserver reproducibility of diagnosis according to the WHO classification are reported as fair. In a large multicenter study, Rieker et al3 showed good diagnostic agreement for the thymoma classification, with a j value of 0.87; however, the agreement for subgroups B1, B2, and B3 had a j value of 0.49. Another multicenter study from Europe, by Verghese et al,4 showed that the overall level of agreement for the 2004 WHO classification of thymoma, among a group of pathologists with experience and expertise in thoracic pathology, was moderate (j ¼ 0.45). As in previous studies,

hymoma is a rare tumor of thymic epithelial cells, with an estimated incidence of 0.13 cases per 100 000 persons per year.1 Thymomas represent a group of tumors with heterogeneous histologic patterns but a relatively homogeneous clinical picture. The current World Health Organization (WHO) classification of thymic epithelial tumors2 categorizes thymomas as type A and type B: type A thymomas are composed of spindled epithelial cells and Accepted for publication June 14, 2013. From the Departments of Pathology (Drs Wang and Moreira), Epidemiology and Biostatistics (Dr Sima), and Surgery (Dr Huang), Memorial Sloan-Kettering Cancer Center, New York, New York; the Department of Pathology, Mount Sinai School of Medicine, New York, New York (Dr Beasley); the Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland (Dr Illei); the Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York (Dr Saqi); The Christie Hospital, and School of Cancer and Enabling Sciences, Department of Histopathology, University of Manchester School of Medicine, Manchester, United Kingdom (Dr Nonaka); and the Department of Pathology and Laboratory Medicine, University of North CarolinaChapel Hill, Chapel Hill (Dr Geisinger). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Andre L. Moreira MD, PhD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (e-mail: [email protected]). 658 Arch Pathol Lab Med—Vol 138, May 2014

Digital Microscopy of Thymic Tumors—Wang et al

a major difficulty arises when classifying distinct subgroups of B thymomas. Staging is the most important prognostic factor in thymomas. The modified Masaoka-Koga staging of thymic epithelial tumors relies heavily on determination of the degree of invasion observed during surgical excision.5,6 Therefore, staging can also be challenging, especially for pathologists without sufficient experience. In recent years, digital pathology has grown tremendously. The whole slide imaging (WSI) system is increasingly being used for distance education, real-time frozen section diagnosis, expert consultation, board examination, and research purposes.7–10 Modern instrumentation and sophisticated software have made digital images sharp, clear, and user-friendly. Whole slide imaging can mimic standard microscopy both in stepwise increase in magnification and in lateral motion in the x and y planes.11 Digital microscopy technology has been validated as a diagnostic tool in multiple studies and for many subspecialties, including prostate needle biopsies, breast core biopsies, and skin and gastrointestinal tract lesions.7–9,12,13 The overall diagnostic accuracy of digital microscopy for neoplasms is very good— generally in the 90th percentile—compared with the gold standard, traditional light microscopy. However, as with traditional histopathologic evaluation, agreement using digital pathologic evaluation is relatively low for nonneoplastic lesions, such as dermal inflammatory conditions or pulmonary interstitial disease.14,15 Virtual slide imaging technology has the potential to advance the dissemination of knowledge of rare tumors such as thymic epithelial neoplasms. Therefore, we assessed its diagnostic reproducibility by use of a multicenter approach. MATERIALS AND METHODS The files of the Department of Pathology, Memorial SloanKettering Cancer Center, New York, New York, were searched for surgical resection specimens of thymic epithelial neoplasm obtained during a 2-year period (2007–2009). Twenty surgical cases of tumors that had been completely excised and for which all slides were available for review were included in the study. All cases were diagnosed and classified by a pathologist with expertise in thoracic pathology, using the 2004 WHO classification of thymic epithelial tumors.2 There were 14 cases of thymoma and 6 cases of thymic carcinoma. One representative hematoxylin-eosin slide from each case was selected to be scanned. All cases were deidentified and assigned a unique number. After review of the diagnoses for the 20 cases and the key diagnostic criteria with the participating pathologists, a second round of the study was performed with an additional 10 cases. The study was approved by the institutional review board. Clinical information pertinent to the patients was collected according to Health Insurance Portability and Accountability Act regulations.

Virtual Microscopy Automated WSI capture was performed with the ScanScope XT system (Aperio, Vista, California). The system’s spatial sampling period (the area of tissue section subtended by a pixel) was approximately 0.50 um/pixel at 320 resolution. The system was operated in its automated batch mode, with automated focus and tissue finding. Images were compressed during the capture process, in the multilayered JPG2000 format, and were saved on a compact disc. The compact discs and a questionnaire were distributed to 5 pathologists at academic-based hospitals. The images were evaluated with Spectrum Plus TM þ TMA (version 9.1; Aperio) Web-based, digital-pathology-information management software. Arch Pathol Lab Med—Vol 138, May 2014

Questionnaire An electronic questionnaire accompanied the compact disc distributed to each study pathologist. Following evaluation of the cases, the pathologists could choose the diagnosis from a dropdown menu based on the 2004 WHO classification of thymic tumors. The choices were ‘‘thymoma A,’’ ‘‘AB,’’ ‘‘B1,’’ ‘‘B2,’’ ‘‘B3,’’ ‘‘thymic carcinoma,’’ or ‘‘other.’’ The pathologists were asked to assess invasion from the provided images and had the choice of ‘‘nondiagnostic for invasion’’; ‘‘no invasion present’’; and ‘‘invasion into capsule,’’ ‘‘fat,’’ ‘‘lung,’’ ‘‘pleura,’’ or ‘‘pericardium.’’ The presence of the latter two was indicated on the slides by blue ink placed during prosection of the surgical specimens. The certainty and confidence of diagnoses made with the Aperio system were assessed by asking the participating pathologists to indicate whether they would like to see the glass slide to make the diagnosis, to indicate whether they thought the digital image was comparable or inferior to a glass slide, and to provide an estimate of the number of thymic epithelial tumors they evaluate in their practices. All of the pathologists were blinded to clinical reports, the original diagnoses, and the identity and interpretations of the other participating pathologists. All participating pathologists had at least 5 years of experience in thoracic pathology.

Statistical Analysis Detailed information regarding diagnosis (thymoma type A, B1, B2, B3, AB, or thymic carcinoma) and the presence and location of invasion was collected from each of the pathologists. Interobserver agreement was evaluated with respect to diagnosis of thymoma versus thymic carcinoma, classification of specific types of thymoma (type A/AB, type B), and presence or absence of invasion. Interobserver agreement was presented by using descriptive statistics (eg, the number of cases in which all pathologists agreed with a certain diagnosis) and was formally evaluated by using Fleiss j statistics, a measure used to quantify agreement among more than 2 raters assigning categorical ratings. There is no generally agreed on interpretation for j values, but a commonly used scale classifies the values as follows: 0 to 0.2, poor agreement; 0.2 to 0.4, fair agreement; 0.4 to 0.6, moderate agreement; 0.6 to 0.8, substantial agreement; and 0.8 to 1, excellent agreement.

RESULTS Agreement Rate for the Diagnosis of Thymoma Versus Thymic Carcinoma The agreement rate among the pathologists varied for specific categories of the WHO classification. The concordance rate for diagnosing type A/AB thymomas (versus any other diagnosis) was moderate (j ¼ 0.46). In 3 cases, at least 4 of the pathologists agreed on the diagnosis of a type A/AB thymoma. In 12 of 20 cases (60%), all pathologists agreed on a diagnosis of non–type A/AB thymoma. There was fair agreement for all categories of type B thymomas (j ¼ 0.38). In 11 of 20 cases, at least 4 of the pathologists agreed on a diagnosis of type B thymoma. When detailed classification of thymomas is taken into consideration, there was perfect agreement among all pathologists for only 3 cases: 1 B1, 1 B2, and 1 B3 thymoma. In these specific cases, the tumors had the classical features described in the WHO classification—that is, a lobulated pattern of growth divided by thick fibrous bands and the corresponding ratio of lymphocytes to epithelial cells (Figure 1). There was perfect agreement for 1 case of thymic carcinoma, which had severe cytologic atypia with nuclear pleomorphism, prominent nucleoli, and infiltrative borders (Figure 2, A and B). In 6 cases, there was discordant diagnosis of the WHO subtype of thymoma among the pathologists. The common feature of these cases was a combination of patterns—for Digital Microscopy of Thymic Tumors—Wang et al 659

the overall agreement for diagnosis of thymoma versus thymic carcinoma. Agreement Rate for the Diagnosis of Invasion by Use of Digital Microscopy

Figure 1. Shown is a classical thymoma correctly diagnosed by all pathologists in the study (World Health Organization type B1 thymoma). At low magnification, visible are sheets of tumor cells separated by thick fibrotic septa in a lobulated growth pattern and a predominance of small lymphocytes admixed with scattered large, round thymic epithelial cells (hematoxylin-eosin, original magnification 3100).

example, tumors with focal areas resembling a spindle cell component but with areas of polygonal cells, with variable amounts of lymphocytes or tumors and more than 1 pattern of type B thymoma (Figure 3, A through C). In most cases of thymomas with combined patterns, only 1 component was interpreted; thus, poor agreement resulted. In 70% of cases (n ¼ 14), there was complete agreement among the pathologists for the diagnosis of thymoma and thymic carcinoma. Thirteen cases were diagnosed as thymoma, and 1 case was diagnosed as thymic carcinoma, leading to an overall agreement that was fair to moderate (j ¼ 0.39). In 5 cases, the discordant diagnosis was between thymoma and thymic carcinoma (2 B2, 2 B3, and 1 type A). Both cases of thymic carcinoma that were diagnosed as type B2 thymoma had marked lymphoid infiltration, as seen at lower magnifications. The 2 cases of thymic carcinoma diagnosed as type B3 thymoma had focal peripheral retention of a lobular growth pattern but had invasive areas composed of a small nest of tumor cells embedded in a marked desmoplastic stroma, increased mitotic activity, and focal cytologic atypia (Figure 2, C and D). One case of thymic carcinoma that was diagnosed as type A thymoma had spindle-shaped cells, but the tumor had significant cytologic atypia and an infiltrative pattern of growth. The overall agreement for diagnosis of thymoma versus thymic carcinoma appeared to be improved in the second round of the study, after review and discussion of the key diagnostic criteria for the first 20 cases. The j value appeared to increase from 0.39 (fair to moderate agreement) to 0.67 (substantial agreement) in the second round (Tables 1 and 2). All tumors that received an original diagnosis of thymic carcinoma expressed immunoreactivity to CD5 and/or CD117 (KIT). However, to avoid bias, this information was not shared with reviewers initially. As expected, once the immunoreactivity pattern of the thymic tumors was released to the participants, there was a perfect agreement (j ¼ 1) to 660 Arch Pathol Lab Med—Vol 138, May 2014

Agreement regarding the presence or absence of invasion was achieved in 12 of 20 cases. All pathologists agreed to the presence of invasion in 10 cases and the absence of invasion in 2 cases. In 6 cases, 4 of 5 pathologists agreed with invasion and 1 pathologist diagnosed no invasion; whereas in 2 cases, 3 pathologists diagnosed invasion and the other 2 diagnosed no invasion. The overall j coefficient for the diagnosis of invasion (present versus absent) was 0.45 (moderate agreement). In cases with the highest levels of disagreement, the disagreement was related to areas of focal invasion, whether capsular invasion or invasion into surrounding adipose tissue (Figure 4, A and B). All cases of invasion into major organs, such as lung, pleura, and pericardium, when present, were identified by all pathologists. The agreement rate for invasion in the second round of the study was 0.57. This result suggests that the overall agreement can be improved after training. The j values of individual agreement for the first 20 cases and for the second round of 10 new cases are shown in Tables 3 and 4. Subjective Evaluation of Digital Microscopy by the Pathologists All the pathologists commented that the digital images were comparable with glass slides. The overall confidence in the diagnoses was good, with opinions ranging from 70% to 100% confidence, which suggests that the difficulty for the diagnoses was not related to the imaging system but rather to an intrinsic characteristic of the tumors. All pathologists in the study diagnosed thymic epithelial tumors at least once a month. Two pathologists reported diagnosing thymic epithelial tumors at least once a week. COMMENT The main purpose of this study was to evaluate the reproducibility of histopathologic classification and assessment of invasion of thymic epithelial neoplasms among experienced thoracic pathologists using digital microscopic systems (WSIs). The current WHO classification of thymic epithelial neoplasms was established in 2004.2 However, because of the rarity of the tumor, the classification of thymic epithelial tumor is still a challenge for many pathologists. The reproducibility rate can be high in a small group of thoracic pathologists after a consensus meeting.16 Interobserver agreement is significantly lower in studies of large groups of general pathologists.3,4 We observed that the rate of interobserver agreement using digital microscopy is comparable to reported rates of interobserver agreement using glass slides, suggesting that the moderate rate of agreement is a product of the intrinsic difficulty of classifying these rare tumors, rather than the methods used for evaluation. In fact, all pathologists participating in the study were satisfied with the quality of the digital images. There are several factors that contributed to the moderate concordance rates in the first round of analysis. First, cases with the most disagreement were histologically heterogeneous, with combined patterns. When confronted with a heterogeneous thymoma, some participating pathologists Digital Microscopy of Thymic Tumors—Wang et al

Figure 2. A classical case of thymic carcinoma is illustrated in (A) and (B), where cytologic atypia is characterized by nuclear pleomorphism and presence of prominent nucleoli. Note the infiltrative pattern of growth and the absence of lymphocytes. This is an example of a case that was correctly diagnosed by all pathologists in the study. A thymic carcinoma with poor agreement is illustrated in (C) and (D). Although the tumor shows an infiltrative growth pattern and nuclear atypia similar to that in (A) and (B), the diagnosis varied from thymic carcinoma to different subtypes of type B thymoma (hematoxylin-eosin, original magnifications 3100 [A and C] and 3400 [B and D]).

documented only 1 pattern, which may represent the predominant component of the tumor or the perceived higher-grade component.16 This may be the most important factor to explain the low agreement rate seen for type B thymomas. Second, the major reason for discordance of diagnosis between thymic carcinoma and thymoma is the tumor growth pattern. Although most pathologists recognized cytologic atypia as a criterion for diagnosis of thymic

carcinoma, the lack of an organotypic pattern of growth and the infiltrative pattern of invasion of the tumor were not consistently taken into consideration as features of thymic carcinoma, which was also the case for mitotic counts. It is possible that, for tumors with cytologic atypia, in actual practice most pathologists would request immunohistochemical stains for CD5 and/or CD117. These immunohistochemical markers are expressed in thymic carcinomas but

Table 1. Agreement for the Diagnosis of Thymoma Versus Thymic Carcinoma in the First Round of the Studya

Table 2. Agreement for the Diagnosis of Thymoma Versus Thymic Carcinoma in the Second Round of the Studya Pathologist

Pathologist Pathologist 1 2 3 4 5 a

1 1 0.89 0.2 0.25 0.25

2

3

4

5

0.89 1 0.21 0.21 0.21

0.20 0.21 1 1 1

0.25 0.21 1 1 1

0.25 0.21 1 1 1

Overall j ¼ 0.39.

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Pathologist 1 2 3 4 5 a

1 1 0.63 0.63 0.90 0.63

2

3

4

5

0.63 1 1 0.41 1

0.63 1 1 0.41 1

0.90 0.41 0.41 1 0.41

0.63 1 1 0.41 1

Overall j ¼ 0.67. Digital Microscopy of Thymic Tumors—Wang et al 661

Figure 3. A, A thymoma with lobulated growth pattern is shown. Note the pale and dark areas. The pale area is illustrated in (B), showing a pattern with predominant epithelial cells mixed with scant lymphocytes, corresponding to a type B3 thymoma, whereas, in (C), there is a small lymphocytepredominant area mixed with scattered round epithelial cells, which is typical of a type B1 thymoma. This combined thymoma had poor agreement among pathologists in the study (hematoxylin-eosin, original magnifications 3100 [A] and 3400 [B and C]).

not in thymomas.2,17,18 In our study, to avoid bias, information on the immunoreactivity of the tumors was not initially provided to the pathologists. Once the information was released, there was a perfect agreement for the diagnosis of thymic carcinoma among participating pathologists. In addition, the threshold for atypia varies among pathologists. However, the results of the second round of the study suggest that agreement can be improved by education and awareness of other criteria, such as invasive growth pattern with desmoplasia and marked Table 3.

mitotic activity. There is no established test to compare the 2 j values to generate a P value. Regardless of the histologic subtype of thymic epithelial neoplasm, staging is the single most important prognostic factor. Staging is based on the evaluation of tumor invasion through the capsule or into surrounding tissue, such as fat, lung, pleura, or pericardium. Interobserver agreement was much better for the evaluation of invasion, which suggests that the imaging quality and speed of WIS are sufficient for pathologists to make the correct judgment. All pathologists

Agreement for the Diagnosis of Invasion in the First Round of the Studya

Table 4.

Agreement for the Diagnosis of Invasion in the Second Round of the Studya

Pathologist Pathologist 1 2 3 4 5 a

1 1 0.69 0.32 0.55 0.69

Pathologist

2

3

4

5

0.69 1 0.40 0.62 1

0.32 0.40 1 0.38 0.21

0.55 0.62 0.38 1 0.50

0.69 1 0.21 0.50 1

Overall j ¼ 0.45.

662 Arch Pathol Lab Med—Vol 138, May 2014

Pathologist 1 2 3 4 5 a

1 1 0.63 0.64 0.50 0.50

2

3

4

5

0.63 1 0.64 0.51 0.51

0.64 0.64 1 0.71 0.71

0.50 0.51 0.71 1 1

0.50 0.51 0.71 1 1

Overall j ¼ 0.57. Digital Microscopy of Thymic Tumors—Wang et al

Figure 4. A thymoma with focal capsule invasion is shown. A, At low magnification, a capsulated thymoma with focal transcapsular invasion is visible. B, Higher magnification of the area, illustrating the tumor invading through the capsule (hematoxylin-eosin, original magnifications 3100 [A] and 3400 [B]).

recognized invasion into adjacent organs, such as lung, pleura, and pericardium. However, most of the disagreement occurred when focal invasion into the capsule or surrounding adipose tissue was present. One of the challenges in the evaluation of invasion is that some thymomas may have an incomplete capsule, which allows for interpretative variation on what constitutes capsular invasion. Interobserver variation in microscopic evaluation of invasion and surgical margins is a real concern in many centers. This has been addressed by a series of articles by the International Thymic Malignancy Interest Group that call for uniform definitions and policies when dealing with thymomas. Correlation with the gross findings and communication with the surgeon are essential steps to be taken in this difficult setting.19,20 We conclude that WSI technology provides sufficient information and substantial quality for the assessment of the histomorphologic profile of the thymic epithelial neoplasm, for diagnosis and staging. Digital imaging technology with image banking can significantly increase the understanding of these rare thymic tumors by general pathologists who do not diagnose thymic neoplasms frequently enough to develop expertise in the classification of these tumors, as well as to foster collaborative work in the field. It is feasible that WSI can be used as a tool to improve the diagnostic consensus among general pathologists. The results of the 2 studies—with comparisons of diagnoses before and after training for specific diagnostic criteria—demonstrate interpretative improvement and confirm the value of WSI as an educational tool in the field of pathology. References 1. Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol. 2010;5(10 suppl 4):S260–S265. 2. Travis WD, Brambilla E, Muller-Hermelink H, Harris CC. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press, 2004. World Health Organization Classification of Tumours; vol 10. 3. 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(6);900–906.

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4. Verghese ET, den Bakker MA, Campbell A, et al. Interobserver variation in the classification of thymic tumors—a multicentre study using the WHO classification system. Histopathology. 2008;53(2);218–223. 5. Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer. 1981;48(11): 2485–2492. 6. Detterbeck FC, Nicholson AG, Kondo K, Van Schil P, Moran C. The Masaoka-Koga stage classification for thymic malignancies: clarification and definition of terms. J Thorac Oncol. 2011;6(7 suppl 3):S1710–S1716. 7. Rodriguez-Urrego PA, Cronin AM, Al-Ahmadie HA, et al. Interobserver and intraobserver reproducibility in digital and routine microscopic assessment of prostate needle biopsies. Hum Pathol. 2011;42(1):68–74. 8. Al-Janabi S, Huisman A, Vink A, et al. Whole slide images for primary diagnostics of gastrointestinal tract pathology: a feasibility study. Hum Pathol. 2012;43(5):702–707. 9. Al-Janabi S, Huisman A, Vink A, et al. Whole slide images for primary diagnostics in dermatopathology: a feasibility study. J Clin Pathol. 2012;65(2): 152–158. 10. Jara-Lazaro AR, Thamboo TP, Teh M, Tan PH. Digital pathology: exploring its applications in diagnostic surgical pathology practice. Pathology. 2010;42(6): 512–518. 11. Costello SS, Johnston DJ, Dervan PA, O’Shea DG. Development and evaluation of the virtual pathology slide: a new tool in telepathology. J Med Internet Res. 2003;5(2):e11. 12. Lopez AM, Graham AR, Barker GP, et al. Virtual slide telepathology enables an innovative telehealth rapid breast care clinic. Hum Pathol. 2009; 40(8):1082–1091. 13. Wienert S, Beil M, Saeger K, Hufnagl P, Schrader T. Integration and acceleration of virtual microscopy as the key to successful implementation into the routine diagnostic process. Diagn Pathol. 2009;4:3. 14. Velez N, Jukic D, Ho J. Evaluation of 2 whole-slide imaging applications in dermatopathology. Hum Pathol. 2008;39(9):1341–1349. 15. Wilbur DC, Madi K, Colvin RB, et al. Whole-slide imaging digital pathology as a platform for teleconsultation. Arch Pathol Lab Med. 2009;133(12): 1949–1953. 16. Chen G, Marx A, Chen WH, et al. New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer. 2002;95(2):420–429. 17. Pan CC, Chen PC, Chiang H. KIT (CD117) is frequently overexpressed in thymic carcinomas but is absent in thymomas. J Pathol. 2004;202(3):375–381. 18. Marx A, Rieker R, Toker A, Langer F, Strobel P. Thymic carcinoma: is it a separate entity: from molecular to clinical evidence. Thorac Surg Clin. 2011; 21(1):25–31. 19. Detterbeck FC, Moran C, Huang J, et al. Which way is up: policies and procedures for surgeons and pathologists regarding resection specimens of thymic malignancy. J Thorac Oncol. 2011;6(suppl 3):S1730–S1738. 20. Huang J, Detterbeck FC, Wang Z, Loehrer PJ Sr. Standard outcome measures for thymic malignancies. J Thorac Oncol. 2010;5(12):2017–2023.

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Classification of thymic epithelial neoplasms is still a challenge to thoracic pathologists: a reproducibility study using digital microscopy.

Thymic epithelial tumors are rare, constituting interpretive challenges for pathologists. Digital imaging can be useful as an educational tool for the...
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