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Indication - Cancer
Basic panel for immunohistochemical (IHC) testing for diagnosis of lymphoma
Facility level:
2. Laboratory
Assay formats
IHC testing (ki-67, CD45, BCL6, IRF4/MUM1, MYC, CD20, CD5, CD10, BCL2, CD23, CD79a, cyclinD1, CD3, CD15, CD30, TdT, CD138/syndecan-1, kappa and lambda chains, PAX5)
Status history
First added in 2019
Changed in 2020
Purpose type
Aid to diagnosis, Prognosis
Purpose
To aid in the diagnosis, sub-classification, prognosis and treatment of lymphoma (including HIV-associated conditions)
Specimen types
Formalin-fixed paraffin-embedded tissue (FFPE)
WHO prequalified or recommended products
N/A
WHO supporting documents
WHO classification of tumours of haematopoietic and lymphoid tissues. WHO classification of tumours, revised 4th edition, volume 2. https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-Haematopoietic-And-Lymphoid-Tissues-2017; WHO Guide for establishing a pathology laboratory in the context of cancer control https://www.who.int/publications/i/item/guide-for-establishing-a-pathology-laboratory-in-the-context-of-cancer-control
Codes
ICD11 code: 2B3Z

Summary of evidence evaluation

Evidence was provided that the proposed panel of markers is adequate to subtype the majority of lymphomas efficiently. As immunohistopathology is considered the reference standard, no estimate of accuracy was reported. The benefits of using this panel of markers for subtyping is presumed to be based on evidence of the benefits of different treatment approaches for different lymphoma types.

Summary of SAGE IVD deliberations

The widely different types of lymphoma require different treatment approaches, and the sub-groups can often be differentiated only by IHC. Diagnosis of lymphoma and other haematological malignancies by immunophenotyping and IHC is established in high-income countries and is essential for individualized care for response and long-term survival. This panel of monoclonal antibodies aids in appropriate diagnosis and sub-classification of lymphomas and allows faster triaging of patients for adapted treatment. Once a diagnosis is suspected, a trained laboratory technologist can use an appropriate algorithm to produce additional stains to aid the pathologist who is assessing the case. This will shorten the turn-around time for diagnosis, which will improve the timeliness of treatment decisions. The test can be used in laboratories with limited skills and is cost–effective.

SAGE IVD recommendation

The SAGE IVD recommended inclusion of the basic panel of IHC tests for diagnosis of lymphoma, noting that identification of lymphoma subtypes can indicate the appropriate treatment. They also noted the requirement for qualified laboratory staff.

Details of submission from 2020

Background

Evidence was provided that the proposed panel of markers is adequate to subtype the majority of lymphomas efficiently. As immunohistopathology is considered the reference standard, no estimate of accuracy was reported. The benefits of using this panel of markers for subtyping is presumed to be based on evidence of the benefits of different treatment approaches for different lymphoma types.

Public health relevance

Prevalence: According to IARC, more than 1.6 million cases are diagnosed, treated or survive. In high-income countries, more patients survive, as a result of timely access to effective, good-quality diagnosis, safe treatment and care during survival. Socioeconomic impact: Lymphoma can arise as an AIDS-defining condition in 3% of cases and is the cause of death in up to 16% of patients with HIV infection, especially in countries where coverage of antiretroviral medicines is suboptimal (2). As prognosis depends on timely access to curative treatment, the prognosis of lymphoma may be conditioned by socioeconomic status; a lower life expectancy of lymphoma patients with lower socioeconomic status has been reported (3), indicating inequality for the poorest populations.

WHO or other clinical guidelines relevant to the test

WHO has set the international diagnostic criteria for classification and stratification of lymphomas (4). The WHO classification is based on a combination of morphology and immune histochemistry, refined by molecular diagnostics as appropriate.

Evidence for clinical usefulness and impact

Haematological malignancies must be identified and classified so that appropriate lineage- and subtype-oriented protocols adapted to the aggressiveness of the lymphoma can be used. Some low-grade lymphomas can be adequately managed by close surveillance or de-escalated regimens, and some are never seen, requiring timely curative treatment (diffuse B-cell lymphoma, Hodgkin lymphoma, Burkitt lymphoma). Some subtypes (cerebral primitive lymphoma, primary effusion lymphoma) are specific to HIV-infected patients and are managed as HIV-related, AIDS-defining conditions. WHO recognizes the importance of identifying subtypes of lymphomas, and IARC has published a classification of tumours of haematopoietic and lymphoid tissues (4) to guide diagnosis with IHC panels to support morphology findings for accurate diagnosis and treatment. Limited- panel IHC is recognized as a basic requirement for the diagnosis and prognosis of lymphoma by leading haematology and oncology societies such as the College of American Pathologists. Rituximab is on the WHO EML for CD20-positive lymphoid malignancies, and WHO prequalification of similar biotherapeutic products has been initiated, highlighting the importance of a basic panel that includes CD20. The panel has been proposed by international oncology and haematology societies and working groups for use in LMICs to provide optimal care for adult and child patients with haematological malignancies. Its use reduces the requirement for external referral and migration for health, enhancing patients’ financial protection. A basic panel that covers more than two thirds of a diagnosis is aligned with the principles of UHC. The current clinical guidelines require correct identification of subtypes of lymphoma to reduce the risk of overtreatment of indolent disease, treat CD20-positive lymphoma with targeted agents and adapt the intensity for more aggressive types (5–14).

Evidence for economic impact and/or cost–effectiveness

The cost of reading a panel of three to five antibodies and five slices in LMICs would be about US$ 15 for consumables, reagents and antibodies (15). Use of the CD status kit requires a laboratory technician for incubation and staining on an automatic strainer and a trained pathologist to read the slides and interpret the results.

Ethical issues, equity and human rights issues

Consent is required to obtain a tissue sample. The availability of lymphocyte differentiation antigens is an essential requirement for personalizing the treatment of lymphomas. Knowledge of a patient’s CD20 status permits the choice of targeted agents, including rituximab. For low-grade disease with an indolent course, less invasive management can be used, including close surveillance, which reduces the risk of overtreatment.
1. Phillips AA, Smith DA. Health disparities and the global landscape of lymphoma care today. Am Soc Clin Oncol Educ Book.2018;37:526–34. 2. Bower M, Fisher M, Hill T, Reeves I, Walsh J, Orkin C, et al. CD4 counts and the risk of systemic non- Hodgkin's lymphoma in individuals with HIV in the UK. Haematologica. 2009;94(6):875–80. 3. Tao L, Foran JM, Clarke CA, Gomez SL, Keegan TH. Socioeconomic disparities in mortality after diffuse large B-cell lymphoma in the modern treatment era. Blood 2014;123(23):3553–62. 4. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO classification of tumours, revised 4th edition, Vol. 2, WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: international Agency for Research on Cancer; 2017 (http://publications. iarc.fr/Book-And-Report-Series/Who-Iarc-Classification-Of-Tumours/Who-Classification-Of- Tumours-Of-Haematopoietic-And-Lymphoid-Tissues-2017, accessed May 2019). 5. Di Santo MG, Ambrosio MR, Rocca BJ, Ibrahim HA, Leoncini L, Naresh KN. Optimal minimal panels of immunohistochemistry for diagnosis of B-cell lymphoma for application in countries with limited resources and for triaging cases before referral to specialist centers. Am J Clin Pathol. 2016;145(5):687–95. 6. Naresh KN, Raphael M, Ayers L, Hurwitz N, Calbi V, Rogena E, et al. Lymphomas in sub-Saharan Africa – what can we learn and how can we help in improving diagnosis, managing patients and fostering translational research? Br J Haematol. 2011;154(6):696–703. 7. NCCN resource – stratified guidelines for B-cell non-Hodgkin lymphoma, basic resource. V5. Plymouth Meeting (PA): National Comprehensive Cancer Network; 2018 8. ESMO clinical practice guidelines: haematological malignancies. Lugano: European Society for Medical Oncology; 2019 (https://www.esmo.org/Guidelines/Haematological-Malignancies, accessed May 2019). 9. Spinner MA, Advani RH, Connors JM, Azzi J, Diefenbach C. New treatment algorithms in Hodgkin lymphoma: too much or too little? Am Soc Clin Oncol Educ Book. 2018;38:626–36. 10. Laboratory workup of lymphoma. In: ASH clinical practice guidelines. Washington DC: American Society of Hematology; 2019 (http://www.hematology.org/Clinicians/Guidelines- Quality/Guidelines.aspx#lymphoma, accessed May 2019). 11. Tan D. Management of B cell non-Hodgkin lymphoma in Asia: resource-stratified guidelines. Lancet Oncol. 2013;14(12):e548–61. 12. Yeoh AE, Tan D, Li CK, Hori H, Tse E, Pui CH. Management of adult and paediatric acute lymphoblastic leukaemia in Asia: resource-stratified guidelines from the Asian Oncology Summit 2013. Lancet Oncol. 2013;14(12):e508–23. 13. Nadiminti K, Nasr M, Mott SC, Syrbu S, Rosenstein LJ. A novel immunohistochemistry (IHC) algorithm for assigning cell of origin status in diffuse large B-cell lymphoma (DLBCL) that better predicts survival as compared to the Hans algorithm (Abstract). In: Abstracts for the 2019 ASCO annual meeting. Alexandria (VA): American Society of Clinical Oncology; 2019 (https:// meetinglibrary.asco.org/record/96127/abstract, accessed May 2019). 14. Hussong JW, Arber DA, Bradley KT, Brown MS, Chang CC, de Baca MR, et al. Protocol for the examination of specimens from patients with non-Hodgkin lymphoma/lymphoid neoplasms. Northfield (IL): College of American Pathologists; 2013 (https://cap.objects.frb.io/protocols/ nonhodgkinlymph-17protocol-3201.pdf, accessed May 2019). 15. Ch’ng ES, Khiro FI. Letter to Editor. Low cost immunohistochemistry bench for developing countries. Malaysian J Pathol. 2018;40(2):209–11.