Accuracy of Pathologic Diagnosis in Patients With Lymphoma and Survival: A Prospective Analysis From Botswana

Abstract

Purpose: With intense HIV epidemics, southern African countries have a high burden of classic Hodgkin lymphoma (CHL) and non-Hodgkin lymphoma (NHL). However, suboptimal access to pathology resources limits subtype classification. We sought to assess the diagnostic accuracy of specimens classified as lymphoma and to determine association between discordant pathologic diagnosis and overall survival.

Methods: Seventy patients with CHL or NHL and treated at three Botswana hospitals from 2010 to 2016 were analyzed. Local pathologic assessment relied primarily on morphology. All cases underwent secondary US hematopathology review, which is considered gold standard.

Results: The median follow-up was 58 months. The overall reclassification rate was 20 of 70 cases (29%). All 20 CHL cases were correctly classified in Botswana, and mixed cellularity was the most common subtype, diagnosed in 11 (55%) cases. Of 47 confirmed NHL cases, diffuse large B-cell lymphoma was the final US diagnosis in 28 cases (60%), another aggressive B-cell NHL in nine (19%), an indolent B-cell NHL in six (13%), and T-cell NHL in four (9%). Common types of diagnostic discordance included NHL subtype reclassification (11 of 20, 55%) and CHL reclassified as NHL (7 of 20, 35%). Concordant versus discordant diagnosis after secondary review was associated with improved 5-year overall survival (60.1% v 26.3%, P = .0066). Discordant diagnosis was independently associated with increased risk of death (adjusted hazard ratio 2.733; 95% CI, 1.102 to 6.775; P = .0300) even after stratifying results by CHL versus NHL.

Conclusion: In this single prospective cohort, discordant pathologic diagnosis was associated with a nearly three-fold increased risk of death. Limited access to relatively basic diagnostic techniques impairs treatment decisions and leads to poor patient outcomes in low-resource countries.

FIG 1

An example of DLBCL initially classified as CHL, mixed cellularity type. (A) H&E-stained sections demonstrated a diffuse inflammatory cell infiltrate with effacement of the underlying nodal architecture. (B) On higher magnification, the infiltrate was composed of large atypical mononuclear cells with prominent macronucleoli (arrows) in a background of small lymphocytes. Although no classic binucleate Reed-Sternberg cells were seen, the resemblance of the large atypical cells to mononuclear Hodgkin cell variants and relatively frequent background non-neoplastic inflammatory cells led to a diagnosis of CHL on the basis of routine H&E stains. (C-E) Immunohistochemical stains demonstrated that the large atypical cells were negative for (C) CD30 and (D) CD15, but stained positively for (E) PAX5, a pan B-cell marker. (F) An additional stain for CD20 was strongly positive, confirming the diagnosis of DLBCL. CHL, classic Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; H&E, hematoxylin and eosin.

FIG 2

An example of SLL initially classified as DLBCL. (A) H&E-stained sections demonstrated diffuse nodal architectural effacement by an infiltrate containing vaguely nodular pale-staining areas, consistent with proliferation centers. (B) On higher magnification, the lymphocytes appeared monomorphous with clumped chromatin and occasional small nucleoli. The cellular monomorphism and extent of nodal architectural effacement prompted a diagnosis of DLBCL on the basis of routine H&E stains. Further evaluation showed that most of the lymphocytes were smaller than endothelial cells (arrow) with only occasional large cells seen (arrowhead). (C-E) The lymphoma cells were diffusely positive for (C) CD20, confirming B-cell lineage, with aberrant expression of the T-cell markers, (D) CD5 and (E) LEF1, supporting a diagnosis of SLL. (F) A stain for Ki67 was not uniformly elevated as would be expected for DLBCL, but showed a variable proliferation index, with higher staining within proliferation centers but relatively low staining outside of proliferation centers, in line with SLL. DLBCL, diffuse large B-cell lymphoma; H&E, hematoxylin and eosin; SLL, small lymphocytic lymphoma.

FIG 3

Kaplan-Meier survival estimate for patients with concordant versus discordant pathologic diagnosis after MGH review with number of patients at risk and 95% confidence limits. MGH, Massachusetts General Hospital; OS, overall survival.

FIG 4

Proposed diagnostic algorithm for high-grade B-cell lymphomas. When routine H&E examination suggests high-grade lymphoma, CD20 is initially performed to support B-cell lineage. DLBCL and BL can then be distinguished on the basis of a staining panel that includes CD10, BCL2, and either Ki67 or MYC. Cases that are negative for CD20 can be stained for CD138 to support a diagnosis of PBL. BL, Burkitt lymphoma; DLBCL, diffuse large B-cell lymphoma; H&E, hematoxylin and eosin; PBL, plasmablastic lymphoma. Adapted from the study by Sayed et al.