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Optimal Minimal Panels of Immunohistochemistry for Diagnosis of B-Cell Lymphoma for Application in Countries with Limited Resources and for Triaging Cases Before

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Optimal Minimal Panels of Immunohistochemistry for Diagnosis of B-Cell Lymphoma for Application in Countries with Limited Resources and for Triaging Cases Before AJCP /ORIGINAL ARTICLE 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 Downloaded from https://academic.oup.com/ajcp/article-abstract/145/5/687/2195691 by World Health Organization user on 09 January 2019 Maria Giulia Disanto, MD,1 Maria Raffaella Ambrosio, MD, PhD,2 Bruno Jim Rocca, MD, PhD,2 Hazem A. H. Ibrahim, FRCPath, PhD,1,3 Lorenzo Leoncini, MD, PhD,2 and Kikkeri N. Naresh, MD, FRCPath1 From the 1Department of Histopathology, Imperial College Healthcare NHS Trust & Imperial College, London, United Kingdom; 2Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy; and 3Department of Histopathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt. Key Words: Lymphoma; B-cell lymphoma; Immunohistochemistry; Diagnosis; Classification; Developing countries Am J Clin Pathol May 2016;145:687-695 DOI: 10.1093/AJCP/AQW060 ABSTRACT Lymphomas are a collection of different malignancies “arising” from lymphoid cells. They include about 49 entities, Objectives: Establish and validate optimal minimal and over 19 provisional entities and subsets.1 About 85% of immunohistochemistry panels for usage in a staged lymphomas are of B-cell origin. Precision in lymphoma diag- algorithmic manner for precise diagnosis of B-cell nosis requires expertise and infrastructure. The entities are lymphomas in countries with limited resources. Suggest defined based on morphology, immunohistochemistry (on short panels of immunostains to be used in referring units some occasions in situ hybridization), cytogenetics/fluores- that refer suspected lymphomas to specialist diagnostic cent in situ hybridization (FISH), molecular genetics and clin- centers in resourceful countries. ical information. Thorough knowledge and experience in Methods: Significant proportion of six B-cell lymphomas morphology of lymphoid lesions and a good understanding of has characteristic morphology requiring a short panel of the current World Health Organization (WHO) classification 1 confirmatory immunostains. The rest would go through five of lymphoid neoplasms are essential. Accurate diagnosis different algorithms. also requires application of a wide panel of immunohisto- chemical stains, high-quality laboratory infrastructure and Results: 812 cases in which a B-cell lymphoma or an HIV- personnel, and resources. In addition, about 20% of cases associated lymphoma was suspected on morphological need cytogenetic and molecular investigations. grounds were evaluated. This led to arriving at a specific Though the incidence of lymphomas varies widely across diagnosis of 799 B-cell lymphomas. A correct diagnosis was the globe, and though the incidence is higher in countries achievable in 69% cases with the application of three to five with better resources, lymphomas are frequent in countries antibodies; others required additional work-up. with limited resources.2 As many countries with limited re- Conclusions: The panels/algorithms assist pathologists in sources have high population density, and as the numbers of practicing lymphoma diagnostics in countries with limited hematopathologists are unfortunately low, the absolute num- resources and in making lymphoma referrals to specialist bers of lymphomas seen by individual pathologists are con- centers. siderably high. Practicing lymphoma pathology in developing countries is challenging, and two of the authors (K.N.N. and L.L.) have been amply exposed to these challenges.3-7 In many countries within Europe, lymphoma diagnosis is being centralized to specialist-integrated hematologic © American Society for Clinical Pathology, 2016. All rights reserved. Am J Clin Pathol 2016;145:687-695 687 For permissions, please e-mail: [email protected] DOI: 10.1093/ajcp/aqw060 687 Disanto et al /MINIMAL IMMUNOPANELS FOR B-CELL LYMPHOMAS malignancy diagnostic services (SIHMDS). Within many Extensive immunohistochemical work-up had been SIHMDS networks, pathologists at contributing/referring undertaken on these cases. Where required, in-situ hybrid- units would like to maintain their expertise. Pathologists ization for Epstein-Barr virus-encoded RNA (EBER) and from the referring units would prefer to perform some light chains, FISH analysis for MYC, BCL2, BCL6, and IG immunostains, attempt to arrive at a diagnosis, and then for- genes, and antigen receptor gene rearrangement studies had ward the sample to the SIHMDS for final integrated diagno- been undertaken. Initially, reports were evaluated, and each sis.8 Although this helps in maintaining a certain level of of the reports had concise, but meticulous morphological expertise at referring units, it also results in duplication of description and clear documentation of all the additional Downloaded from https://academic.oup.com/ajcp/article-abstract/145/5/687/2195691 by World Health Organization user on 09 January 2019 work-up and a strain on resources. work-up undertaken. Though lymphoma diagnostics have evolved in re- The diagnostic process was employed by two phases, sourceful countries of Europe and North America, some of phase 1 and phase 2. Based on the morphological descrip- the investigators in these countries (such as two of the au- tion (in cases other than those where HIV status was thors of this manuscript, L.L. and K.N.N.) have a keen inter- known), an attempt was made to slot cases into categories est in improving lymphoma diagnostics in developing under phase 1. Cases that could not be placed into any of the countries and in fostering translational research in lymph- categories under phase 1 were then assigned to diagnostic omas prevalent in developing countries.6 The primary aim algorithms based on the morphological description. of the study was to establish minimal panels of immunohis- Biopsies from HIV-positive patients were placed under tochemistry that can be used in a staged algorithmic manner Algorithm 5. to arrive at a precise diagnosis in most cases of suspected B- cell lymphomas in countries with limited resources. Through this work, we also wanted to suggest short panels Phase 1 Diagnosis of immunostains that can be used in referring units in the We identified six types of the B-cell lymphomas that context of SIHMDS networks (or similar centralized ser- had very characteristic morphology and thus required a short vices for lymphoma diagnostics) before the referral is made. panel of immunostains to confirm the diagnosis Table 1 . The limited panel algorithms are not intended for use in These included the following: SIHMDS, where having short turnaround times (TATs), 1. Suspected chronic lymphocytic leukemia/small achieving highest accuracy and diagnostic precision on a lymphocytic lymphoma (CLL/SLL): characteristic cytolo- large volume of cases, training of personnel within the cen- gical features and presence of proliferation centres. Confirm ters and those who refer cases to the centers, and documen- with CD20 (positive), CD5 (positive), CD23 (positive), tation clinically relevant biomarkers and translational CD10 (negative), and cyclin D1 (negative). If CD23 is nega- research, are of paramount importance. tive, evaluate for SOX11 or proceed to Algorithm 2 in phase Overall, the approach we suggest could help in cutting 2. Please note that if flow cytometry/immunophenotyping costs and improving quality in both resource-poor and re- has documented the characteristic immunophenotype of sourceful countries. CLL, lymph node biopsy and immunohistochemistry would not be essential. Suggested algorithms (both on phase 1 and 2 for CLL) are primarily for those cases where peripheral blood/bone marrow immunophenotyping has either not Materials and Methods been performed or has not been informative. The study was initially performed on 296 cases in 2. Suspected follicular lymphoma, grades 1 to 3a (FL1- which a B-cell lymphoma or an HIV-associated lymphoma 3a): a prominent follicular pattern and with presence of cen- was suspected on initial morphological evaluation during trocytes accompanied by variable numbers of centroblasts. the period from January 2012 to June 2012 at the Confirm with CD20 (positive), CD10 (positive), BCL2 Department of Histopathology of Hammersmith Hospital, (positive), and cyclin D1 (negative). If features are not diag- Imperial College Healthcare NHS Trust, London, UK. nostic, the case would need further evaluation by Algorithm Following this, the study was extended to and validated 1 in phase 2. with an additional 516 cases of suspected B-cell lymphomas 3. Suspected follicular lymphoma, grade 3b (FL3b): a seen during the period between January 2005 and June 2012 prominent follicular pattern and with infiltrate entirely com- at the Department of Medical Biotechnologies of the posed of centroblasts (absence of centrocytes). Confirm University of Siena, Italy. All 812 cases had been fixed in with CD20 (positive), BCL6 (positive), BCL2 (positive), formalin and embedded in paraffin. Cases where the initial IRF4/MUM1 (positive) and cyclin D1 (negative). In follicu- morphological description suggested Hodgkin lymphoma or lar lymphoma with a follicular pattern (irrespective of a T-cell lymphoma were excluded. grade), CD21 immunostain is recommended only when the 688 Am J Clin Pathol 2016;145:687-695 © American Society for Clinical Pathology 688 DOI: 10.1093/ajcp/aqw060 AJCP /ORIGINAL ARTICLE Table 1 not conform to the characteristic patterns described in phase Immunohistochemistry
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