Background: The effective management of lymphoma depends upon an accurate and precise pathologic diagnosis. However, the classification of lymphoma continues to evolve. Reports addressing the role of second opinion expert pathology review have found varying impact, and little is known regarding the predictors of a change in diagnosis. Furthermore, the impact of the World Health Organization (WHO) classification of lymphomas over the 5 years following their formal publication has not been formally assessed. Methods: All outside pathology is reviewed at Memorial Sloan-Kettering Cancer Center (MSKCC) before a clinical opinion is finalized. We performed a chart review of all externally referred lymphoma cases from 1/1/01 to 6/30/01 and from 1/1/06 to 6/30/06 with second opinions from MSKCC hematopathology. Statistical analysis was performed using Chi-square or Fisher’s exact test for univariate analysis and logistic regression for multivariate analysis. Results: 719 patients (365 in 2001, 354 in 2006) met inclusion criteria. Diagnostic revisions were classified as major or minor; major changes were those that would lead to management changes as per National Comprehensive Cancer Network guidelines. 122 patients (18% in 2001, 16% in 2006) had a major diagnostic revision and an additional 22 (4% in 2001, 2% in 2006) had confirmation of major revisions rendered previously at second opinion from another National Cancer Institute Comprehensive Cancer Center (CCC). This did not change significantly by era, with 79 major revisions (22%) in 2001 and 65 (18%) in 2006 (P=NS). An additional 55 patients [24 (7%) in 2001, 31 (9%) in 2006] received minor revisions. Common categories of major revision included changing from nondiagnostic/ambiguous to definitive [6 in 2001, 8 in 2006], definitive to nondiagnostic [9 in 2001, 9 in 2006], malignant to benign [1 in 2001, 6 in 2006], indolent B-cell lymphoma (BCL) to aggressive BCL [15 in 2001, 8 in 2006], and aggressive BCL to indolent BCL [4 in 2001, 1 in 2006]. Major diagnostic revision was significantly associated with additional immunohistochemistry (IHC) testing in 2001 (OR=2.3; 95%CI 1.3, 4). In 2006, additional IHC (OR=1.8; 95%CI 1, 3.4), repeat biopsy (OR=3.1; 95%CI 1.2, 8.0), and skin biopsy (versus lymph node biopsy; OR 3.3; 95%CI 1.6, 7.0) were significantly associated with major revision. Two of the 7 patients reclassified as benign received revisions based on additional IHC, whereas 7 of the 14 patients reclassified as malignant were revised due to either additional IHC (4) or repeat biopsy (3). No effect was seen by biopsy type, nor were patient gender, age, race or ethnicity associated with odds of major revision. Of cases seen first at another CCC, 12% in 2001 and 16% in 2006 received major revisions, compared to 19% (2001) and 16% (2006) of other cases; these differences were not statistically significant. Conclusion: The rate of clinically meaningful diagnostic revisions at second opinion expert pathology review was high for patients seen at MSKCC, and remained so despite five years of increased familiarity with the WHO classification schema. These data confirm the fact that an appropriate evaluation, including detailed IHC and an adequate biopsy specimen, plays a central role in the accurate diagnosis of lymphoma. The high rates of diagnostic revision reported here lend support to the routine application of expert second opinion hematopathology review.