Laboratory Workup of Lymphoma in Adults

Guideline From the American Society for Clinical Pathology and the College of American Pathologists

Steven H. Kroft, MD; Cordelia E. Sever, MD; Adam Bagg, MD; Brooke Billman, MLIS, AHIP; Catherine Diefenbach, MD; David M. Dorfman, MD, PhD; William G. Finn, MD; Dita A. Gratzinger, MD, PhD; Patricia A. Gregg, MD; John P. Leonard, MD; Sonali Smith, MD; Lesley Souter, PhD; Ronald L. Weiss, MD, MBA; Christina B. Ventura, MPH, MT(ASCP); Matthew C. Cheung, MD


Am J Clin Pathol. 2021;155(1):12-37. 

In This Article

Abstract and Introduction


Objectives: The diagnostic workup of lymphoma continues to evolve rapidly as experience and discovery lead to the addition of new clinicopathologic entities and techniques to differentiate them. The optimal clinically effective, efficient, and cost-effective approach to diagnosis that is safe for patients can be elusive, in both community-based and academic practice. Studies suggest that there is variation in practice in both settings. The aim of this review is to develop an evidence-based guideline for the preanalytic phase of testing, focusing on specimen requirements for the diagnostic evaluation of lymphoma.

Methods: The American Society for Clinical Pathology, the College of American Pathologists, and the American Society of Hematology convened a panel of experts in the laboratory workup of lymphoma to develop evidence-based recommendations. The panel conducted a systematic review of the literature to address key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, recommendations were derived based on the available evidence, the strength of that evidence, and key judgments as defined in the GRADE Evidence to Decision framework.

Results: Thirteen guideline statements were established to optimize specimen selection, ancillary diagnostic testing, and appropriate follow-up for safe and accurate diagnosis of indolent and aggressive lymphoma.

Conclusions: Primary diagnosis and classification of lymphoma can be achieved with a variety of specimens. Application of the recommendations can guide decisions about specimen suitability, diagnostic capabilities, and correct utilization of ancillary testing. Disease prevalence in patient populations, availability of ancillary testing, and diagnostic goals should be incorporated into algorithms tailored to each practice environment.


The diagnosis and classification of lymphoma has evolved into a complex, multimodality process that requires rigorous attention to and quality assurance of numerous preanalytical, analytical, and postanalytical details. After exclusion of purely leukemic disorders and plasma cell neoplasms, the 2016 revised fourth edition of the World Health Organization's (WHO) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues[1] details more than 60 distinct mature lymphoid neoplasms. Although accurate prediction of outcome has long been a primary goal of lymphoma classification, direction of management was a secondary goal in some respects—historically, because of limited available therapeutic options. This has changed dramatically in recent years given the proliferation of disease-specific regimens and the explosion of novel agents that show targeted activity in distinct subtypes of lymphoma.

Consequently, accurate diagnosis and classification have become more important than ever. Yet, even as the diagnostic process for lymphoma has grown more complex and requires application of an ever-growing array of ancillary diagnostic techniques, clinical practice has shifted progressively toward less invasive procedures. Effectively, pathologists are being asked to do more with less. Given these trends, it is logical to suspect that a tipping point will eventually be reached at which the quality of the diagnostic process will begin to degrade. Overlaid is the increasing need to act as responsible stewards of limited health care resources. Yet, little guidance exists regarding appropriate procurement techniques, specimen requirements, triage processes, and algorithms for deployment of specialized ancillary studies in the diagnosis of lymphomas. Perhaps as a consequence of this lack of guidance, practice patterns vary considerably from center to center. Understanding the limitations and advantages demonstrated by the available evidence will help health care teams and patients choose a diagnostic testing strategy that is best suited to their goals and resources.

To address the uncertainty related to the workup of suspected lymphomas, the American Society for Clinical Pathology (ASCP), the College of American Pathologists (CAP), and the American Society of Hematology (ASH) convened a joint workgroup to develop an evidence-based guideline to address appropriate evaluative processes. The primary goal of this guideline was to develop recommendations for the preanalytic phase of testing, with a focus on specimen requirements. An overarching key question drove the activity of this expert panel (EP): What are the specimen requirements for an accurate diagnosis in all adult patients with clinical features raising consideration of lymphoma?

To address this question, the EP derived a set of key questions, as detailed in the Objectives section. These questions were crafted to query issues related to the relative effectiveness of various procedures, the specimen requirements for effective and accurate diagnosis, the process of triaging tissue for ancillary techniques, and the performance characteristics of those ancillary techniques.