Potential Impact of Pathologic Review on Therapy in Non-Hodgkin’s Lymphoma (NHL): Analysis from the National Comprehensive Cancer Network (NCCN) NHL Outcomes Project.
Authors: LaCasce Ann , Niland Joyce , Kho Michelle E. , terVeer Anna , Friedberg Jonathan W. , Rodriguez Maria A. , Czuczman Myron S. , Millenson Michael , Zelenetz Andrew D. , Nademanee Auayporn P. , Weeks Jane C. 
Published: April 2020

Abstract
Background: Optimal therapy of NHL is critically dependent upon an accurate pathologic diagnosis. High inter-rater reliability has been demonstrated among expert hematopathologists for common B cell NHLs using the WHO classification system. However, less is known about the accuracy and reliability of pathologic diagnosis of lymphoma in the routine care setting.
Methods: We used data from the NCCN NHL Outcomes Project, a prospective cohort study collecting comprehensive clinical, treatment, and outcome data for patients seen at 5 participating centers (City of Hope, Dana-Farber, Fox Chase, MD Anderson, and Roswell Park), to compare pathologic diagnosis assigned at referring and NCCN centers. Newly diagnosed patients presenting between 7/00 and 12/04 with a final diagnosis of one of the following NHL subtypes were included in this analysis: follicular lymphoma (FL, grades 1,2,NOS), FL grade 3, marginal zone (MZL, extranodal, nodal, and splenic), small lymphocytic (SLL), diffuse large B-cell (DLBCL) and mantle cell (MCL). Diagnosis was considered concordant if the NCCN institution assigned the same WHO diagnosis as the referring institution. In order to assess the potential impact of diagnostic reclassification on treatment and outcomes, we defined 6 outside institution treatment-oriented categories: Indolent 1 (FL 1,2,NOS, all types of MZL and SLL), Indolent 2 (FL 3), Aggressive (i.e. DLBCL), MCL, Highly Aggressive (e.g. Burkitt or lymphoblastic lymphoma) and Other Cancer. NCCN diagnoses were classified into 4 treatment-oriented categories: Indolent 1, Indolent 2, DLBCL, and MCL. Treatment category was considered concordant if the diagnosis assigned by the referring institution and the NCCN institution mapped to the same treatment category.
Results: Of 928 patients eligible for this analysis, 741 had specimens reviewed at both a referring and NCCN institution. Among these patients, the final diagnosis was discordant for 9% (66/741, 95%CI [7%,11%]). The rates of discordance by histologic type (as assigned by the NCCN center) were: FL 6% (13/218), FL3 16%(5/31), MZL 8% (5/60), SLL 29% (9/31), DLBCL 8% (25/304) and MCL 9% (9/97). In SLL, almost half of discordance was due to use of non-WHO diagnoses (n=4). Of the 66 discordant cases, 51 (7% of total, 95% CI [5%, 9%]) were ultimately diagnosed with a histology that mapped to a discordant treatment category. This included 15 patients (29%) whose final diagnosis was a more aggressive histology (DLBCL), potentially curable if treated with appropriate first-line therapy.
Conclusions: We found that the vast majority of patients with common NHL were classified accurately by referring centers. For 9% of patients, however, review by an expert hematopathologist resulted in an alternative diagnosis, and for the majority a change in expected treatment potentially impacting therapeutic outcome.
Treatment Category NCCN Referring Institution Indolent 1 (N=309) Indolent 2 (N=31) DLBCL (N=304) MCL (N=97) Indolent 1 94% 10% 4% 7% Indolent 2 1% 84% 1% 0 Aggressive 1% 6% 93% 1% MCL 2% 0 0 91% Highly Aggressive 1% 0 1% 1% Other Cancer 1% 0 &lt;1% 0