Context

Pathologists play an increasingly critical role in optimizing testing on scant specimens to ensure patients not only receive a correct and timely diagnosis, but also that the appropriate evaluation of biologic markers, or “biomarkers,” is performed to inform prognosis and best guide therapeutic options. Advances in biomarkers have been particularly impactful in the field of hematopathology, where the identification of cytogenetic abnormalities, specific mutations, morphologic features, and/or protein expression may help guide clinical decision-making, including type and intensity of therapy and eligibility for clinical trials.

Objective

To stay up to date with advances in relevant biomarkers for diagnosis, prognosis, and therapy. The Cancer Biomarkers Conference (CBC) has been developed as a highly focused meeting to provide key biomarker updates across medical fields with the inclusion of industry partners, to reach a broader audience, and cross-pollinate emerging areas for biomarker application and future discovery. The objective of this article is to raise awareness of the potential utility of such meetings for improving patient care and facilitating collaboration.

Data Sources

Recently released guidelines related to B-cell lymphoma diagnosis from the World Health Organization and International Consensus Classification and associated manuscripts are reviewed. Material presented at the CBC conference is summarized.

Conclusions

This article covers highlights of the updates presented on B-cell lymphoma biomarkers at the most recent Cancer Biomarkers Conference in Flowood, Mississippi, in September 2022.

The Cancer Biomarkers Conference (CBC) series originated under the direction of Philip Cagle, MD, in 2016, with the initial 3 annual meetings held at Methodist Hospital in Houston, Texas. The conference title incorporates the word “biomarkers,” short for biologic markers, which are characterized as objective and quantifiable characteristics of biologic processes.1  Biomarkers are increasingly useful for confirming diagnoses, better predicting prognosis, and directing therapy. These objective measures may relate to direct testing on the diagnostic biopsy specimens, results of other laboratory testing, imaging data, and/or clinical findings. However, the CBC meeting focuses on bringing together experts to optimize biomarker testing relevant to diagnostic biopsy specimens in the setting of malignancy to better direct patient therapy and outcome.

Biomarkers may be distinguished as diagnostic, prognostic, or predictive, with some potential overlap. For example, detection of ALK1 protein expression by immunohistochemistry in anaplastic large cell lymphoma can be used both for diagnosis and to inform a generally more favorable prognosis for the affected patient compared with ALK forms of anaplastic large cell lymphoma. Such prognostic biomarkers typically relate to intrinsic characteristics of the specimen.2  Predictive biomarkers help identify whether a patient may be more likely to have a favorable or unfavorable response to a particular therapy or intervention2  and are increasingly used to direct initial therapy as well as for refractory disease. For example, tumor mutational burden as a reflection of the quantity of potential neoantigens produced by the tumor can help predict response to immune checkpoint inhibitor therapy.3  Biomarkers also include laboratory studies indicating extent of involvement and necessity for initiating therapy, such as hypercalcemia or anemia, indicating that a plasma cell neoplasm should be classified as multiple myeloma with indication to begin therapy. A range of biomarkers are included as part of predictive models used in a number of disease settings, such as the Revised International Prognostic Scoring System for myelodysplastic syndrome risk assessment, which includes bone marrow cytogenetics, blast percentage, and peripheral blood cytopenias,4  to give patients a better understanding of prognosis when there may be significant heterogeneity in outcome based on diagnosis alone. Performing or preserving adequate material to perform this testing on the diagnostic specimens is critical for the appropriate application of these models.

A significant challenge in pathology, particularly in hematopathology, has been the rapid evolution in our understanding of factors important for prognosis and for predicting potential response to improved and targeted therapies. Diagnostic criteria are also continually refined based on this knowledge, potentially necessitating additional testing.57  Optimization of ancillary testing has become increasingly critical given the often small size of specimens, creating a tradeoff between diagnostic and prognostic testing and the preservation of material for potential future testing relevant to clinical trials.

The goal of the CBC meetings has been to bring together pathologists, clinicians, and industry leaders to discuss key and emerging biomarkers of clinical significance and potential mechanisms to implement such testing across both academic and community practice settings. Overall, there is diversity in the range of participants, including most major subfields of pathology from academic centers, pathologists in private practice, trainees at a range of levels, and clinical colleagues, as well as industry leaders. However, the lecture settings are relatively small and combined into a single session so that intimate discussions can occur across disciplines. Following a 2-year hiatus during the pandemic, the fifth of such meetings (CBCV) took place in Flowood, Mississippi, in September 2022, directed by Timothy Craig Allen, MD, JD (Beaumont Hospital, Royal Oak, Michigan).

Initial meetings particularly focused on biomarkers for solid tumors, emerging opportunities and challenges for immune checkpoint inhibitor therapy, and potential optimization of cytology samples for biomarker evaluation. Biomarkers important for the diagnosis and management of leukemias and lymphomas were subsequently incorporated into the CBC and have become a growing component of these conferences. Figure 1 shows an overview of such potential biomarkers. The left column lists general biomarkers of potential relevance to pathologists, the central column lists specific features of the general biomarkers that are applicable to disease, and the right column lists the aspects of patient care for which biomarkers may be required.

Figure 1

Biomarkers are integral to all aspects of diagnostic hematopathology and patient care. Every level of cellular function generates biomarkers. An increasing subset of these can be harnessed to better classify, treat, and/or monitor for therapeutic response and potential disease relapse. Different sets of ancillary tests are of utility in the evaluation of lymphomas (eg, large B-cell lymphomas and chronic lymphocytic leukemia and other small B-cell lymphomas), plasma cell neoplasms, acute leukemias, and myeloid neoplasms. Direct measurement of abnormal metabolites may be on the horizon, but oncometabolites produced by IDH1 and IDH2 mutations are of clinical significance.

Figure 1

Biomarkers are integral to all aspects of diagnostic hematopathology and patient care. Every level of cellular function generates biomarkers. An increasing subset of these can be harnessed to better classify, treat, and/or monitor for therapeutic response and potential disease relapse. Different sets of ancillary tests are of utility in the evaluation of lymphomas (eg, large B-cell lymphomas and chronic lymphocytic leukemia and other small B-cell lymphomas), plasma cell neoplasms, acute leukemias, and myeloid neoplasms. Direct measurement of abnormal metabolites may be on the horizon, but oncometabolites produced by IDH1 and IDH2 mutations are of clinical significance.

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Overall, the CBC provides a unique opportunity for experts across fields to get a broader picture of the success and challenges of available biomarkers, companion testing, and emerging biomarkers. The meeting is somewhat unique from the pathology standpoint in that it includes insight from clinicians as well as industry leaders, including with a “boot camp” held the day prior to the meeting. Industry partners are often present at pathology and clinical meetings, with ongoing discussions held outside of the main sessions and during break periods. The CBC meeting boot camp is relatively unique in that it directly incorporates industry leaders into panel discussions alongside pathology and clinical colleagues. A mixture of pathology, clinical, and industry colleagues are also present as active participants in the audience in the meeting itself. This enables a full and open discussion of not only the potential utility of testing but managing costs and other barriers that may limit access to the highest quality standard of care.

Following the boot camp, the meeting has 1.5 days of focused, 30-minute talks given by a range of experts. The overview of advances in biomarkers in the diagnosis and treatment of hematopoietic malignancies at CBCV included “Biomarkers in Myeloid Neoplasms” from Daniel Arber, MD (University of Chicago, Chicago, Illinois); “Update on T-cell Lymphoma” by Robert Ohgami, MD, PhD (University of Utah and ARUP Laboratories, Salt Lake City); and “Update on B-cell Lymphoma Biomarkers” by the author.

The update on B-cell lymphoma biomarkers session at CBCV focused on key updates from the proposed 5th edition revised World Health Organization (WHO-HAEM5) monograph,7  as well as the separately released International Consensus Classification (ICC) system.6  Both systems build on the established diagnostic categories of the 4th revised edition WHO monograph.8  Although there is substantial overlap, the presence of 2 classification systems presents challenges to the practicing pathologist and treating clinicians, as well as for the inclusion of patients in ongoing clinical trials.

This article will highlight several specific aggressive B-cell lymphomas considered at CBCV for which newly discovered biomarkers have changed the way that diseases are regarded diagnostically and/or prognostically/predictively (Table). The diagnostic workup for aggressive B-cell lymphomas continues to be a rapidly evolving area in hematopathology. A revised diagnostic algorithm for aggressive B-cell lymphoma is shown (Figure 2). One approach is to consider specific subtypes of aggressive B-cell lymphomas first, including the subset of lymphoproliferative disorders that may be viral-associated. Other subtypes may be identified by a combination of morphologic, immunophenotypic, molecular, and/or clinical features. Remaining aggressive B-cell lymphomas are then placed into the “wastebasket” category of diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS).

Comparison of International Consensus Classification (ICC)6  and the 5th Edition World Health Organization (WHO-HAEM5)5  in B-Cell Lymphoma, Both Building on the 4th Revised Edition of the WHO Hematolymphoid Monograph8,a

Comparison of International Consensus Classification (ICC)6 and the 5th Edition World Health Organization (WHO-HAEM5)5 in B-Cell Lymphoma, Both Building on the 4th Revised Edition of the WHO Hematolymphoid Monograph8,a
Comparison of International Consensus Classification (ICC)6 and the 5th Edition World Health Organization (WHO-HAEM5)5 in B-Cell Lymphoma, Both Building on the 4th Revised Edition of the WHO Hematolymphoid Monograph8,a
Figure 2

Diagnostic algorithm for aggressive B-cell lymphomas based on the International Consensus Classification (ICC)6  and proposed revisions of the 5th edition World Health Organization (WHO) hematolymphoid monograph (WHO-HAEM5).7  Differences between the WHO-HAEM5 and ICC systems are noted, with parentheses indicating the alternative WHO-HAEM5 term as published in 2022,7  with recognition that additional refinements in the WHO-HAEM5 are ongoing. Abbreviations: CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; FL, follicular lymphoma; HGBL, high-grade B-cell lymphoma; KSHV/HHV-8, Kaposi sarcoma herpesvirus/human herpesvirus-8; LBCL, large B-cell lymphoma; LPD, lymphoproliferative disorder; NOS, not otherwise specified; PTLD, posttransplantation lymphoproliferative disorder.

Figure 2

Diagnostic algorithm for aggressive B-cell lymphomas based on the International Consensus Classification (ICC)6  and proposed revisions of the 5th edition World Health Organization (WHO) hematolymphoid monograph (WHO-HAEM5).7  Differences between the WHO-HAEM5 and ICC systems are noted, with parentheses indicating the alternative WHO-HAEM5 term as published in 2022,7  with recognition that additional refinements in the WHO-HAEM5 are ongoing. Abbreviations: CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; FL, follicular lymphoma; HGBL, high-grade B-cell lymphoma; KSHV/HHV-8, Kaposi sarcoma herpesvirus/human herpesvirus-8; LBCL, large B-cell lymphoma; LPD, lymphoproliferative disorder; NOS, not otherwise specified; PTLD, posttransplantation lymphoproliferative disorder.

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Although seemingly complex, efforts to better define subcategories of aggressive B-cell lymphomas have enabled better prediction of clinical outcomes and potential response to therapy. This in turn enables more focused clinical trials and additional identification and/or clarification of the most relevant biomarkers for clinical decision-making (Figure 3). For example, DLBCL, NOS is one of the most common types of lymphoma diagnosed, but it remains a heterogeneous category in terms of clinical course and response to therapy.911  Both WHO-HAEM5 and ICC continue to recommend evaluation of cell of origin in DLBCL, NOS by immunohistochemistry or gene expression profiling methods12,13  to help inform prognosis. In addition, such characterization is generally required by clinical trials. Evaluation of c-Myc and Bcl-2 expression by immunohistochemistry to identify a potential “double expresser” phenotype has been de-emphasized. Importantly, additional data from large-scale sequencing studies911,14  are emerging, where the mutational landscape appears to better predict prognosis in DLBCL, NOS. However, these data are not yet broadly incorporated into the diagnostic algorithms.

Figure 3

Revisions to diagnostic categories and biomarker discovery are interconnected. In an ideal setting, diagnostic classification systems should enable more-uniform diagnosis across practice settings, inform prognosis and treatment, and enable clinical trials to yield more meaningful information by better defining disease entities. Continual reevaluation of biomarkers helps to make this possible. New biomarkers can be identified based on the results of clinical trials to further refine diagnostic categories as the process continues. The recently revised diagnostic classification systems in hematopathology57  are evidence of the success of this process.

Figure 3

Revisions to diagnostic categories and biomarker discovery are interconnected. In an ideal setting, diagnostic classification systems should enable more-uniform diagnosis across practice settings, inform prognosis and treatment, and enable clinical trials to yield more meaningful information by better defining disease entities. Continual reevaluation of biomarkers helps to make this possible. New biomarkers can be identified based on the results of clinical trials to further refine diagnostic categories as the process continues. The recently revised diagnostic classification systems in hematopathology57  are evidence of the success of this process.

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WHO-HAEM5 does include revision to the diagnostic workup of Burkitt lymphoma based on emerging molecular data.7  Three epidemiologic variants of Burkitt lymphoma have been historically recognized, including endemic, sporadic, and immunodeficiency-associated. These cases vary in the fraction associated with Epstein-Barr virus (EBV), with most endemic cases being EBV positive. By contrast, 20% to 30% of sporadic cases are EBV positive, and 25% to 40% of immunodeficiency-associated cases are EBV positive, which predominantly occur in the setting of HIV, as compared with other forms of immune suppression.8,15,16  Although the MYC translocation is the hallmark of Burkitt lymphoma, it is not generally sufficient for tumorigenesis. Burkitt lymphoma shows a pattern of molecular changes as well, and these are distinct from DLBCL, including from DLBCL of germinal center cell of origin.10,15,17,18  Interestingly, EBV-positive Burkitt lymphomas also have distinct molecular features compared with EBV-negative Burkitt lymphomas. EBV-positive cases show fewer driver mutations, including fewer mutations in SMARCA4, CCND3, ID3, and TCF3, and fewer mutations associated with apoptosis, but an overall greater mutational burden associated with defects in mismatch repair. Together, the presence of defects in mismatch repair with intact apoptotic pathways raises the possibility that EBV-positive Burkitt lymphoma may be more susceptible to DNA-damaging agents.1518  As a result, WHO-HAEM5 places a greater emphasis on the division of Burkitt lymphoma into EBV-positive and EBV-negative subgroups, which appear to represent discrete biologic subgroups based on their molecular features.7 

Molecular profiling has also helped to further characterize large B-cell lymphomas with 11q aberration (ICC6 )/high grade B-cell lymphoma with 11q aberrations (WHO-HAEM57 ). This category was initially designated “Burkitt-like lymphoma with 11q aberration” as a provisional category in the 4th revised edition of the WHO8  based on gene expression data used to identify a gene expression pattern associated with Burkitt lymphoma.19  This small subset of aggressive B-cell lymphomas lacks the characteristic MYC translocation and shows a peculiar pattern of chromosome 11q aberration. However, subsequent data showed that, in contrast to the gene expression pattern, the mutational pattern of these cases appears to be closer to that of DLBCL. The morphologic pattern also shows an increased degree of cytologic polymorphism, which may be more in keeping with DLBCL than mimicking that of Burkitt lymphoma. Overall, the nature of these rare cases remains to be further characterized, but they are recognized by both ICC and WHO-HAEM5 to better enable that characterization.6 

Other important changes for routine diagnosis of lymphoproliferative disorders include the recognition of EBV-positive polymorphic B-cell lymphoproliferative disorder, NOS across settings by the ICC.6  This category will include EBV-positive B-cell proliferations with the appropriate morphologic features, with or without known immunodeficiency. An example of such a lesion from an HIV-positive patient involving the brain is shown (Figure 4). In the absence of adequate antiretroviral therapy, patients with HIV/AIDS are at high risk of EBV-associated primary central nervous system DLBCL, which is typically seen at very low CD4 counts and is associated with an aggressive course.20  However, this patient had adequate viral control, and the lesion showed a polymorphic appearance not compatible with a diagnosis of primary central nervous system DLBCL. In addition, the process followed an indolent clinical course. The ability to separately designate such processes is helpful for both predicting prognosis and directing therapy. WHO-HAEM5 goes beyond this to endorse a broader, more standardized framework to aid in describing such lesions and create a consistent terminology across immune deficiency/dysregulation settings. Given the expanded iatrogenic methods of altering immune function, congenital forms of immunodeficiency, immune senescence, and other sources of immune dysfunction, this framework may enable better tracking of risk factors associated with particular medications or patient populations beyond known associations (eg, risk of young men with inflammatory bowel disease on thiopurines for development of hepatosplenic T-cell lymphoma21  and potential risk of renal transplant recipients on mycophenolate of developing a primary central nervous system posttransplantation lymphoproliferative disorder22).

Figure 4

Epstein-Barr virus (EBV)–positive polymorphic B-cell lymphoproliferative disorder, not otherwise specified is now recognized in patients with or without known immunodeficiency.6  A, A hematoxylin-eosin–stained section from a central nervous system lesion in a patient with well-controlled HIV shows a mixed population of lymphoid cells, histiocytes, and plasma cells with focal necrosis. B, A dual stain with immunohistochemistry for CD20 (red chromagen) and in situ hybridization for EBV-encoded small RNAs (EBER, brown chromagen) show variably sized B cells, including a subset with EBV reactivation. The findings are consistent with an EBV-positive polymorphic lymphoproliferative disorder, not otherwise specified by the International Consensus Classification.6  In the 5th edition of the World Health Organization hematolymphoid monograph,7  the process shown would be designated “Polymorphic lymphoproliferative disorder, EBV-associated, arising in the setting of well-controlled HIV infection.”

Figure 4

Epstein-Barr virus (EBV)–positive polymorphic B-cell lymphoproliferative disorder, not otherwise specified is now recognized in patients with or without known immunodeficiency.6  A, A hematoxylin-eosin–stained section from a central nervous system lesion in a patient with well-controlled HIV shows a mixed population of lymphoid cells, histiocytes, and plasma cells with focal necrosis. B, A dual stain with immunohistochemistry for CD20 (red chromagen) and in situ hybridization for EBV-encoded small RNAs (EBER, brown chromagen) show variably sized B cells, including a subset with EBV reactivation. The findings are consistent with an EBV-positive polymorphic lymphoproliferative disorder, not otherwise specified by the International Consensus Classification.6  In the 5th edition of the World Health Organization hematolymphoid monograph,7  the process shown would be designated “Polymorphic lymphoproliferative disorder, EBV-associated, arising in the setting of well-controlled HIV infection.”

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Given the time constraints of the session, only limited updates on biomarkers associated with low-grade B-cell lymphoma diagnosis and management were discussed. Potentially impacting the day-to-day practice of most hematopathologists is the reconsideration of morphologic grading in follicular lymphoma. Grading consists of enumerating the number of centroblasts per high-power field, which can be a source of dread as well as the potential for discrepancy given differences in the size of the microscopic field, heterogeneity within the tumor follicles, tumor sampling, and subjectivity of the observer. Grade 3B follicular lymphoma, composed entirely of centroblasts, is more reproducibly recognized between pathologists and appears to be distinct in clinical behavior, being more similar to that of DLBCL. The distinction between grades 1 to 2 (0–15 centroblasts) and 3A (>15 centroblasts)8  is of less clear clinical relevance. Consensus opinion of the ICC was to retain the morphologic grading system (grades 1–2, 3A, and 3B) but with discussion that the difference in prognosis between grades 1 to 2 and 3A is debatable.6,23,24  The ICC also highlights the importance of testing for IRF4 rearrangements in grade 3B expressing IRF4/MUM1, because these may represent large B-cell lymphoma with IRF4 rearrangement and show a more favorable outcome.25  Awareness of this issue is also raised in the WHO-HAEM5. ICC also recognizes a subtype of testicular follicular lymphoma with unique features and seen in young boys.

In addition, WHO-HAEM5 proposes an alternative grouping and approach to follicular lymphoma diagnosis. Most follicular lymphoma cases show an at least partial follicular pattern, are composed of both centrocytes and centroblasts, and carry a t(14;18) (IGH::BCL2) translocation.7  These cases are grouped into the new category of “classic follicular lymphoma” in WHO-HAEM5, with further morphologic grading within this category being optional. Additional subtypes of follicular large B-cell lymphoma (incorporating follicular lymphoma grade 3B) and follicular with uncommon features are recognized. Grading is not applicable to these latter 2 categories.

The CBC represents a unique meeting format to stimulate discussion, provide key biomarker updates, and enable pathologists to interact directly with clinicians and industry leaders. The unique setting, bringing together experts across subdisciplines within pathology, also helps cross-pollinate ideas and potentially opens new avenues for the application of existing biomarkers.

Substantial advances have been made in the application of biomarkers across fields to the diagnosis and treatment of malignancies; however, there remain significant differences between subspecialties. For example, immune checkpoint inhibitor therapy and associated companion diagnostics have been disproportionately applied in solid tumors, with more recent interest in application to classic Hodgkin lymphoma and lymphomas in immune-privileged sites.26  The potential utility of cytology specimens for biomarker testing,27  including next-generation sequencing,28  is also an important area for further discussion and collaboration because cytology specimens are often obtained prior to or in conjunction with limited surgical specimens. Highlights of the meeting also included a discussion from Jose Otero, MD, PhD (The Ohio State University, Columbus), on advances in diagnostic algorithms in neuropathology.29  Such algorithms will be increasingly relevant in pathologic diagnosis across subdisciplines to optimize use of limited tissue for biomarker testing and streamline the diagnostic process.

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Competing Interests

The author has no relevant financial interest in the products or companies described in this article.

Author notes

Presented in part at the Cancer Biomarkers Conference V; September 10–11, 2022; Flowood, Mississippi.