Implications of Plasma Lymphoblastic Cells In

REVIEW ARTICLE Implications of Plasma Lymphoblastic Cells in Lymphoreticular Disorders: An Overview Marin Abraham1, SV Sowmya2, Roopa S Rao3, Dominic Augustine4, Vanishri C Haragannavar5

Abstract Aim: The aim of this review was to emphasize the diverse morphologic features of plasma lymphoblastic cells in lymphoreticular disorders to arrive at a precise diagnosis. Background: The lymphoreticular system comprises of a group of cells with a common lineage and primary function of immunoregulation. Specific immunity is achieved by the combined effects of macrophages and lymphocytes, and, therefore, it is the lymphoreticular system. These cells are scattered in different parts of the body and share some functional characteristics. At both functional and anatomical levels, lymphoreticular tissue can be categorized into primary and secondary lymphoid organs that predominantly produce lymphocytes and plasma cells. Review results: The plasma lymphoblastic lesions/malignancies comprise of characteristic cells like buttock cells, cells with irregular nuclei, cells with cleaved nuclear outlines, etc. Identification of such cells amidst sheets of malignant lymphoblastic cells is challenging. However, sound knowledge about the morphology of these cells and their immunohistochemical panel of markers may provide a clue for diagnosis. Conclusion: The predominant cell types noted in plasma lymphoblastic lesions histopathologically are immature lymphocytes and plasma cells in their varied cell activity suggest the biologic behavior of the lesion. Clinical significance: Understanding and identifying the normal and pathological cellular and nuclear morphology of the lymphoreticular cells can aid in the definitive diagnosis of the plasma lymphoblastic disorders and predict its biological nature. Keywords: Hematopoietic stem cells, Immunoglobulins, Lymphoreticular system, Lymphoblasts, Plasmablasts. World Journal of Dentistry (2019): 10.5005/jp-journals-10015-1636

Introduction 1–5Department of Oral Pathology and Microbiology, M. S. Ramaiah The lymphoreticular system is distributed throughout the body, University of Applied Sciences, Bengaluru, Karnataka, India of which many of its cells originating from the hematopoietic stem Corresponding Author: Marin Abraham, Department of Oral cells, normally circulate in the peripheral blood and are involved Pathology and Microbiology, M. S. Ramaiah University of Applied in immune responses of various kinds including the synthesis Sciences, Bengaluru, Karnataka, India, Phone: +91 9880323479, e-mail: of immunoglobulins.1 Cells that constitute the lymphoreticular [email protected] system are bone marrow-derived cells that include lymphocytes, How to cite this article: Abraham M, Sowmya SV, et al. Implications monocytes, macrophages, and histiocytes. The white blood cells of Plasma Lymphoblastic Cells in Lymphoreticular Disorders: An originate from the lymphocytic and myelocytic lineages. The Overview. World J Dent 2019;10(3):241–245. lymphocytes and plasma cells are produced in the lymphogenous Source of support: Nil tissues namely the lymph glands, spleen, thymus, tonsils, bone Conflict of interest: None marrow, and payers patches.2 Two major lymphocyte populations, particularly those dependent on the presence of thymus gland (T cells) and those controlled by B cells, differentiate to form The proliferation of stem cells and its derivatives in circulating antibody-secreting cells. The plasma cells and memory B cells blood can cause enlargement of liver, spleen, and lymph nodes which represent an end stage and are responsible for humoral immunity, is characteristic in infections; however, an abnormal proliferation when appropriately sensitized T cells confer cell-mediated of cells in the lymphatic system, lymph, blood, and bone marrow immunity on host protecting from infections.3 Repeated can lead to hematopoietic and lymphoid malignancies.6 Neoplastic encounter of the same antigen triggers the rapid reactivation of disorders, although less frequent, are much more important to preexisting specific memory B cells, which then potentially enter manage clinically. Abnormal proliferations of plasmablasts are new germinal center reactions and differentiate into short-lived recognized in immunodeficient and immunocompetent conditions, plasmablasts or remain in the system as memory B cells.4 whereas aberrance in immature lymphocytes is a typical feature in The predominant precursors of the lymphoreticular system leukemia and lymphomas.4,7 include lymphoblasts and the plasmablasts. Lymphoblasts are about Histological findings, blood picture, and biochemical 10–18 μm in size, with a large or oval nucleus and a stippled and alterations are best considered as different facets of a single clumped nuclear chromatin. They are rapidly dividing in nature and underlying disease process.1,8 The malignancies encountered due are the earliest detectable precursor of lymphoid cells. Plasmablasts to the abnormal proliferation of lymphoblasts and plasmablasts have a round to oval morphology, measuring about 15–25 μm with exhibit heterogeneity and versatile histopathological a basophilic cytoplasm more marked in the periphery than in the presentations. In the present review, the plasma lymphoblastic center (Table 1).5 cells with characteristic cellular and nuclear pleomorphisms

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons. org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. An overview on Plasma Lymphoblastic Cells in Lymphoreticular Disorders

Table 1: Summary of characteristic cellular and nuclear pleomorphisms in various lymphoreticular disorders Immunohistochemical Characteristic cells Lymphoreticular disorders Characteristic morphologic features Clinical significance panel/markers Cells with con- Mantle cell lymphoma Small lymphocytes with dense Increased mitotic rate4,9 SOX1110 densed chromatin Small B cell lymphocytic chromatin condensation (Fig. 1) lymphoma Peripheral T cell lymphoma Cells with prominent Large B cell lymphoma Dispersed chromatin Increased mitotic rate Large B cell lymphoma- nucleoli (Fig. 1) stathmin10 Small B cell lymphocytic More basophilic due to abundant Increased protein synthesis T cell lymphoma [not lymphoma rough endoplasmic reticulum and cell activity otherwise specified Peripheral T cell (RER)4,9 (NOS)]-CD311 lymphoma Cell with cleaved Follicular lymphoma Indented nuclei Infrequent mitosis Cluster of differentia- nuclear outlines Rate of growth is slow4,9 tion 10 (CD10), B cell (Fig. 1) lymphoma 6 protein (BCL6), human germinal center associated lymphoma (HGAL), LIM only transcription factor 2 (LMO2), and stathmin10 Irregular nuclei/ Acute lymphoblastic These cells are large and heterogene- Increased mitotic rate CD10, BCL6, HGAL, agranular cytoplasm leukemia ous showing irregular nuclear shape Aggressive nature4,9 LMO2, and stathmin10 (Fig. 2) with variable nuclear chromatin, cytoplasmic content, and basophilia4,9 Plasmacytoid lym- Plasmacytoma More abundant cytoplasm Presence of immunoglobulin CD2012 phocytes (Fig. 2A) Development of RER in cytoplasm on tumor cell surface and Increased RNA acids exhibiting within the cytoplasm in some 4,9 amphophilic/basophilic cytoplasm cases Presence of clumped chromatin in the nucleus against nuclear membrane Classical Reed Hodgkin’s lymphoma Multinucleated/binucleated cells There is increase in deoxy CD30 and CD156 Sternberg (RS) cells with an amphophilic cytoplasm ribonucleic acid content (Fig. 2B) and large and prominent nucleoli proportionate to number of (owl-eye appearance) nuclear lobes The nuclei undergoes endomitosis and polyploidization4,9 Plasmacytic plasma- Plasmacytoma Pleomorphism of plasma cells Presence of excess of immu- CD20, CD138, and blasts (Fig. 2A) noglobulin in the blood CD5613 Multiple myelomas Presence of plasma cells in clumps Mitosis is uncommon4,9 and sheets Presence of Mott cells Abnormal synthesis, traffick- ing, or excretion of the immunoglobulin that is stored in excess within the cytoplasm14 Presence of flame cells Horse-shoe-shaped Anaplastic large cell Typical hallmark tumor cells with Aggressive lesion CD3015 nuclei (Fig. 3B) lymphoma lobulated (embryo-like) nuclei and a Increased mitotic rate4,9 prominent nucleolus Dutcher bodies Lymphoplasmacytoid Cytoplasmic inclusions that are Accumulation of IgM in cyto- CD20, CD79a, and (Fig. 3A) lymphoma either invaginated into or are plasm of plasmalymphocytic PAX516 overlying the nucleus cells MALT lymphoma Increase in protein content4,9 Buttock cells Follicular lymphoma, Separate nuclear lobes connected Increased mitotic rate4,9 CD10, BCL6, HGAL, (Fig. 2A) mycosis fungoides, and by chromatin LMO2, and stathmin10 Sézary syndrome Villous lymphocytes Splenic lymphoma, hairy Monomorphic lymphoid cells with Beta actin expression that CD1917 (Fig. 3C) cell leukemia poorly defined cytoplasm is polymerized to F actin in cortical cytoskeleton16 Contd...

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Contd... Immunohistochemical Characteristic cells Lymphoreticular disorders Characteristic morphologic features Clinical significance panel/markers Associated with Irregular cytoplasmic villi polyarteritis nodosa, exposure to coal dust Flagellated/hairy appearance Polylobulated/pop- Hodgkin’s lymphoma Large and pleomorphic cell with Protein like homogeneous CD20 and CD4517 corn/lymphocyte- abundant basophilic cytoplasm and material indicating abnormal predominant/LP cell vesicular nuclear chromatin metabolic activity within the (Fig. 3C) cells18 Single nucleus with folding and EM reveals presence of many multilobation, resembling popcorn, degenerated mitochondria and hence the name “popcorn” and vacuoles cells17 Variant of RS cell Lacunar cells (Fig. Hodgkin’s lymphoma- The cells exhibit a pale cytoplasm It shrinks from surrounding CD30 and CD156 3D) mixed cellularity type structures during processing in formalin-fixed tissues Variant of RS cells Exhibits a clear space or a lacunae in which the cells reside19 Cells with Russell Lymphoplasmacytoid Globular aggregates of immuno- Abnormal immunoglobulin Lymphoid enhancer bodies (Fig. 1) lymphoma globulin in the nucleus or cytoplasm production in the tumor cells binding factor of the tumor cells exhibits different types of (LEF1)10 inclusions It represents disorders of cytoplasmic immunoglobulin synthesis Assembly/secretion, associated disordered metabolism of the neoplastic B cells20 Tingible body mac- Burkitt’s lymphoma Large macrophages with ingested There is active phagocytosis CD10-positive for ma- rophages (Fig. 1) cellular debris of apoptotic bodies and ture B cells expressing lymphoid cells surface immunoglobulin On fixation cytoplasm is lost Stathmin6,10 leaving white spaces filled with debris Starry sky appearance4,9

encountered in the various hematopoietic malignancies are summarized with their significance so as to arrive at a precise diagnosis.

Conclusion The disorders of the lymphoreticular system show cellular and nuclear morphological variations that lead to enigma in diagnosis. A wide variety of disorders displaying such features include lymphomas, leukemias, and plasmacytomas. Some of the morphological changes observed in the immature/stem cells of the lymphoreticular system are cells with cleaved nuclei, reticular cells, polylobated/popcorn cells, lacunar cells, buttock cells, etc. The presence of some of these cells may determine the biologic behavior of the lesion. Therefore, the identification of these cells facilitates the accurate diagnosis of their associated lesions. Sound Fig. 1: Photomicrograph of non-Hodgkin’s lymphoma (H&E stain, knowledge of the diverse morphology of the lymphoreticular ×400) showing lymphoblasts with prominent nucleoli (red arrow), condensed chromatin (yellow arrow), cleaved nuclear outline (green cells in routine staining along with their immunohistochemical arrow), plasmablast with Russell bodies (brown arrow), and tingible expression can aid in the definitive diagnosis of the lymphoreticular body macrophages (blue arrow) disorders.

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Figs 2A and B: Photomicrographs of solitary plasmacytoma of bone showing various precursor cells of lymphoreticular system in (A) like Buttock cells (blue arrow), cells with irregular nuclei and agranular cytoplasm (orange arrow), plasmacytic plasmablast (red arrow), plasmacytoid lymphocyte (green arrow); (B) Reed Sternberg cell (black arrow) of Hodgkin’s lymphoma (H&E stain, ×400)

Figs 3A to D: Photomicrographs of Hodgkin’s lymphoma showing Dutcher bodies; (A) Horse-shoe-shaped nuclei of lymphoblastic cell; (B) Polylobulated popcorn cells (red arrow) and Villous lymphocytes (green arrow) in (C) and lacunar cells (D) (H&E stain, ×400)

References 5. Mohan H. Pathology for Dental Students, 3rd ed. New Delhi: Jaypee Brothers Medical Company, 2005. 1. Gowing NFC. Tumors of reticuloendothelial system, Nomenclature, 6. Kumar V, Abbas AK, et al. Robbins Basic pathology, 9th ed. Histogenesis and Behaviour. J Clin Path 1974;27(7):103–107. Philadelphia: Saunders; 2013. 2. Hall JE. Textbook of Medical Physiology, South Asian ed. Elseviers; 2013. 7. Malathi L, Amsaveni R, et al. Reticular endothelial Malignancy of 3. Roitt I. Lymphoreticular system: functional organization. J Clin Pathol Head and Neck: A Comprehensive Review. J Pharm Bioallied Sci 1972;25(11):1003–1004. 2015;7(1):S145–S157. 4. Walter JB, Israel MS. General Pathology, 6th ed. Edinburgh: Churchil 8. Rajendran R, Shivapathasundharam B. Shafers text book of oral Living Stone; 1987. pathology, 6th ed., NewDelhi; 2010.

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9. Ritchie AC. Boyd’s Text Book of Pathology, 9th ed. Lea and Febiger; 15. Jairajpuri ZS, Rana S, et al. Extranodal anaplastic large cell lymphoma 1990. mimicking sarcoma: a report of an interesting case. Int J Appl Basic 10. Zhang X, Aguilera N. New Immunohistochemistry for B Cell Med Res 2014;4(1):S50–S52. lymphoma and Hodgkin’s Lymphoma. Arch Pathol Lab Med 2014;138: 16. Wang E, Stoecker M, et al. Follicular lymphoma with prominent 1666–1672. Dutcher body formation: a pathologic study of 3 cases in comparison 11. Agostinelli C, Piccaluga PP, et al. Peripheral T cell lymphoma, not with nodal or splenic lymphoplasmacytic lymphoma and marginal otherwise specified: the stuff of genes, dreams and therapies. J Clin zone lymphoma. Hum Pathol 2012 Nov 1;43(11):2001–2011. Pathol 2008;61(11):1160 –1167. 17. Naeim F, Nagesh Rao P, et al. Nodular Lymphocyte Predominant 12. Flowcytometry ST. Immunohistochemistry and molecular genetics Hodgkin Lymphoma. Atlas of Hematopathology. New York: Academic for Hematologic Neoplasms, 2nd ed. Philadelphia: Lippincott Press; 2013. pp. 593–599. Williams and Wilkins; 2012. 18. Ledezma MAG, Hinojosa CAT, et al. Hairy cell leukemia, an uncommon 13. Abraham M, Augustine D, et al. Diagnostic Panel of B-cell lymphoid neoplasia. Medicina Universitaria 2016;18(70): Markers,CD45,CD20,CD3,CD138 and CD56 for oral Solitary 34–41. Plasmacytoma of Bone. World J Dent 2018;9(1):53–58. 19. Yang YH, Palmer SD. The morphology of Reed Sternberg Cells in Bone 14. Ribourtout B, Zandecki M. Plasma Cell Morphology in Multiple marrow. Am J Clin Pathol 1963;39(2):115–120. Myeloma and Related Disorders. Morphologie 2015;99(325): 20. Tweel Jan VD, Taylor CR, et al. Immunoglobulin inclusions in non- 38–62. Hodgkins lymphoma. Am J Clin Pathol 1977;69(3):306–313.

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