Background: Thymomas are heterogenous tumors derived from the thymic epithelial cells. Although prognosis is relatively good compared to other epithelial cancers, there is a great variability in survival depending on the degree of differentiation; furthermore there is a high degree of heterogeneity within the tumor. The WHO classification updated in 2004 describes this heterogeneity introducing combined thymoma categories.1 The 1999 classification was shown to be able to predict the clinical course in several retrospective studies.2-5 However, this classification has been subject of criticism, due to the potential lack of reproducibility, especially in the presence of limited tumor material (resection specimen vs biopsy). We investigated the reproducibility of the WHO classification when performed by different pathologists and its prognostic implication on a large series of resected thymic malignancies. Materials and methods: The series consisted of 134 patients who underwent surgery at one institution (Humanitas Hospital, Milan, Italy). The original histological diagnosis (CLAS1) produced at the time of surgery was available in all cases, as well as the clinical history. Samples were selected for collaborative molecular studies to be performed at NIH, and the histological classification was reviewed by a single pathologist of the same institution (CLAS2) before samples were sent out. Two independent pathologists at NIH reclassified all cases (CLAS3, CLASS4) based on a single H&E slide from each case, in a blinded fashion. We evaluated the global correlation of these four classifications and the pairwise correlation by Fleiss’ kappa coefficient.6 Disease related survival and progression free survival (PFS) curves were generated according to the Kaplan-Meier method and comparisons between curves were made using the log-rank test. Results: The frequencies reported by the four pathologists are summarized in the table: A AB B1 B2 B3 C B1,B2 B2,B3 CLAS1 14.6% 23.8% 13.8% 8.5% 16.2% 10.8% 4.6% 7.7% CLAS2 10.2% 21.9% 18.0% 6.3% 18.8% 11.7% 4.7% 8.6% CLAS3 12.4% 19.4% 17.1% 15.5% 17.8% 16.3% 0.0% 1.6% CLAS4 17.2% 19.5% 4.7% 31.3% 18.0% 9.4% 0.0% 0.0% The Kappa correlation coefficient was 0.58. The K coefficient between CLAS1 and 2 was 0.813; CLAS2-3 was 0.61; CLAS3-4 0.52; CLAS1-3 0.59; CLAS1-4 0.49 and CLAS2-4 0.45. Histological tumor subtype predicted the disease-related survival in a statistically significant manner using the classification produced by 3 pathologists (CLAS1 p=0.004, CLAS2 p=0.028, CLAS4 p=0.001) but not by CLAS3 (p=0.131). Considering all 4 classifications, the histotype-related 10 year-survival is 100% for type A and between 94-100% for AB, 93-100% for B1, 70-88% for B2, 76-83 for B3, 58-72% for C and 85-86% for B2,B3. The histotype was able to predict the PFS with a statistically significant LogRank=0.025 for CLAS2 and <0.0001 for all the others. The 5y PFS is 100% for type A, AB, B1 and B1,B2 and range between 87-91% for B2, 82-90% for B3, 47-71% for C, 83-85% for B2,B3. Conclusion:The WHO classification identifies histotypes predicting the outcome with increasing aggressive behaviours from type A to C. The combined thymoma categories show aggressiveness intermediate between the individual types. Although the overall correlation between different pathologists is only moderate (K-correlation coefficient 0.41-0.61) this has only a minor effect on the ability to predict survival.

Reproducibility of the WHO classification for thymomas in relation to prognosis

PETRINI, IACOPO;
2009-01-01

Abstract

Background: Thymomas are heterogenous tumors derived from the thymic epithelial cells. Although prognosis is relatively good compared to other epithelial cancers, there is a great variability in survival depending on the degree of differentiation; furthermore there is a high degree of heterogeneity within the tumor. The WHO classification updated in 2004 describes this heterogeneity introducing combined thymoma categories.1 The 1999 classification was shown to be able to predict the clinical course in several retrospective studies.2-5 However, this classification has been subject of criticism, due to the potential lack of reproducibility, especially in the presence of limited tumor material (resection specimen vs biopsy). We investigated the reproducibility of the WHO classification when performed by different pathologists and its prognostic implication on a large series of resected thymic malignancies. Materials and methods: The series consisted of 134 patients who underwent surgery at one institution (Humanitas Hospital, Milan, Italy). The original histological diagnosis (CLAS1) produced at the time of surgery was available in all cases, as well as the clinical history. Samples were selected for collaborative molecular studies to be performed at NIH, and the histological classification was reviewed by a single pathologist of the same institution (CLAS2) before samples were sent out. Two independent pathologists at NIH reclassified all cases (CLAS3, CLASS4) based on a single H&E slide from each case, in a blinded fashion. We evaluated the global correlation of these four classifications and the pairwise correlation by Fleiss’ kappa coefficient.6 Disease related survival and progression free survival (PFS) curves were generated according to the Kaplan-Meier method and comparisons between curves were made using the log-rank test. Results: The frequencies reported by the four pathologists are summarized in the table: A AB B1 B2 B3 C B1,B2 B2,B3 CLAS1 14.6% 23.8% 13.8% 8.5% 16.2% 10.8% 4.6% 7.7% CLAS2 10.2% 21.9% 18.0% 6.3% 18.8% 11.7% 4.7% 8.6% CLAS3 12.4% 19.4% 17.1% 15.5% 17.8% 16.3% 0.0% 1.6% CLAS4 17.2% 19.5% 4.7% 31.3% 18.0% 9.4% 0.0% 0.0% The Kappa correlation coefficient was 0.58. The K coefficient between CLAS1 and 2 was 0.813; CLAS2-3 was 0.61; CLAS3-4 0.52; CLAS1-3 0.59; CLAS1-4 0.49 and CLAS2-4 0.45. Histological tumor subtype predicted the disease-related survival in a statistically significant manner using the classification produced by 3 pathologists (CLAS1 p=0.004, CLAS2 p=0.028, CLAS4 p=0.001) but not by CLAS3 (p=0.131). Considering all 4 classifications, the histotype-related 10 year-survival is 100% for type A and between 94-100% for AB, 93-100% for B1, 70-88% for B2, 76-83 for B3, 58-72% for C and 85-86% for B2,B3. The histotype was able to predict the PFS with a statistically significant LogRank=0.025 for CLAS2 and <0.0001 for all the others. The 5y PFS is 100% for type A, AB, B1 and B1,B2 and range between 87-91% for B2, 82-90% for B3, 47-71% for C, 83-85% for B2,B3. Conclusion:The WHO classification identifies histotypes predicting the outcome with increasing aggressive behaviours from type A to C. The combined thymoma categories show aggressiveness intermediate between the individual types. Although the overall correlation between different pathologists is only moderate (K-correlation coefficient 0.41-0.61) this has only a minor effect on the ability to predict survival.
2009
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/757449
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