EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts

Stefan D Dojcinov, Falko Fend, Leticia Quintanilla-Martinez, Stefan D Dojcinov, Falko Fend, Leticia Quintanilla-Martinez

Abstract

The contribution of Epstein-Barr virus (EBV) to the development of specific types of benign lymphoproliferations and malignant lymphomas has been extensively studied since the discovery of the virus over the last 50 years. The importance and better understanding of the EBV-associated lymphoproliferative disorders (LPD) of B, T or natural killer (NK) cell type has resulted in the recognition of new entities like EBV+ mucocutaneous ulcer or the addition of chronic active EBV (CAEBV) infection in the revised 2016 World Health Organization (WHO) lymphoma classification. In this article, we review the definitions, morphology, pathogenesis, and evolving concepts of the various EBV-associated disorders including EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), EBV+ mucocutaneous ulcer, DLBCL associated with chronic inflammation, fibrin-associated DLBCL, lymphomatoid granulomatosis, the EBV+ T and NK-cell LPD of childhood, aggressive NK leukaemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity of primary EBV+ nodal T- or NK-cell lymphoma. The current knowledge regarding the pathogenesis of B-cell lymphomas that can be EBV-associated including Burkitt lymphoma, plasmablastic lymphoma and classic Hodgkin lymphoma will be also explored.

Keywords: Epstein-Barr virus; clinical features; epidemiology; lymphoma; lymphoproliferations; morphology; pathogenesis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Infectious mononucleosis. (A) The lymph node shows retained architecture, hyperplastic lymphoid follicles and expanded paracortex (H&E, 100×). (B) The paracortex contains a polymorphous infiltrate of lymphocytes and plasma cells with numerous prominent immunoblasts, including some with Hodgkin-like features (H&E, 200×). (C) CD20 (left) and CD3 (right) highlight retention of lymph node architecture and separation of B-cell and T-cell compartments (magnification, 5×). (D) CD20 highlights prominent B-cell immunoblasts including those with Hodgkin-like features. (E) CD3 highlights abundant paracortical small lymphocytic T-cell infiltrate but also scattered large T-cell immunoblasts. (F) The immunoblasts and Hodgkin-like cells are CD30 positive. (G) There is abundant paracortical staining with EBER co-localising with the B-cells (in-situ hybridization, 100×). (H) The same cells are also positive for LMP1 (immunohistochemistry, D, F, H, 200×; E, 400×).
Figure 2
Figure 2
EBV positive diffuse large B-cell lymphoma, not otherwise specified. (A) Polymorphous infiltrate of HRS-like cells in a background of lymphocytes and histiocytes (H&E, 400×). (B) Wide areas of necrosis are common and invasion of vascular walls is seen (inset) (H&E, 100×). (C) The majority of tumour cells are positive for CD20, which highlights markedly variable size of the lesional cells. (D) Most of the tumour cells are positive for CD30. (E) Occasional cells co-expressing CD15 are seen. (immunohistochemistry, C, D, 200×, E, 400×) (F) There is widespread positivity for EBER, which highlights variability in the size of the nuclei. (in-situ hybridization, 200×).
Figure 3
Figure 3
EBV positive mucocutaneous ulcer. (A) EBV MCU on the tongue—a shallow ulcer with raised edges and necrotic debris in the centre. The clinical suspicion is often one of squamous cell carcinoma. (B) The ulcer is well circumscribed and at the base shows a rim of darker staining small lymphocytes (H&E, 10×). (C) On higher magnification, it comprises a polymorphous mixture of lymphoid cells of variable sizes, many with HRS-cell features (H&E, 200×) (inset) in a lymphohistiocytic background (H&E, 600×). (D) Angioinvasion is frequently seen. (E) The lesional cells are significantly positive for CD20, which highlights variable cell size. (F) There is strong expression of PAX5. (G) OCT2 is also strongly positive. (H) Most cells express CD30. (I) There is frequent co-expression of CD15 (immunohistochemistry, D, 100×; E, F, G, H, 200×; I, 400×). (J) EBER is abundantly positive, highlighting variability in nuclear sizes of the lesional cells (in-situ hybridization, 200×).
Figure 4
Figure 4
Fibrin associated diffuse large B-cell lymphoma. (A) Prosthetic mitral valve with fibrinous vegetation. (B) The sections of the fibrin clot show blue staining areas representing cellular lymphoid proliferation (H&E, 5×). (C) The lymphoid proliferation forms a band underneath the surface of the clot (H&E, 40×). (D) It is composed of large pleomorphic lymphoid cells with focal caryorrhexis (H&E, 400×). (E) There is strong expression of CD20 and (F) MUM1. (G) Ki67 highlights high proliferation (immunohistochemistry, E, F, 100×; G, 40×). (H) All cells are EBER positive (in-situ hybridization, 40×).
Figure 5
Figure 5
Lymphomatoid granulomatosis. (A) Chest CT shows nodular cavitating lesions. (B) There is an angiocentric and angioinvasive infiltrate of variably sized lymphoid cells some with Hodgkin-like features (H&E, 100×). The extent of vascular involvement is highlighted by the Elastic-Van Gieson stain (inset) showing the same vessels and consumption of the full thickness of the vascular wall (EVG, 100×). (C) CD20 highlights variably sized lesional B-cells including those with Hodgkin-like features (grade II). (D) These cells are CD30 positive and follow the contour of the vessel. (E) The background lymphoid infiltrate comprises abundant small T-cells highlighted by CD3 (immunohistochemistry, C, 200×; D, E, 100×). (F) The lesional B-cells are positive for EBER, which highlights variation in nuclear size. (in-situ hybridization, 100×).
Figure 6
Figure 6
Plasmablastic lymphoma. (A) Tumour cells show immunoblastic and some plasmacytic features (H&E, 200×). (B) Some tumours show a greater degree of pleomorphism and more marked plasma cell differentiation (H&E, 200×). (C) There is lack of expression of CD20 and (D) CD45. (E) The tumour cells are positive for CD138 and (F) MUM1. (G) There is strong expression of CD56 in some tumours. (H) Aberrant expression of CD3 may be observed. (I) There is significant positivity for MYC (immunohistochemistry, C–G, I 200×, H, 400×). (J) All tumour cells are positive for EBER (in-situ hybridization, 100×).
Figure 7
Figure 7
Burkitt lymphoma. (A) The tumour is composed of regular, medium size cells with basophilic cytoplasm, coarse nuclear chromatin and small peripheral nucleoli; tangible body macrophages are scattered through the tumour generating a starry sky appearance (H&E, 100×). (B) Some tumours show copious granulomatous reaction, which may obscure the lymphoma. (C) There is strong, uniform expression of CD10. (D) No expression of BCL2 is seen. (E) Ki67 shows 100% proliferation fraction. (F) CD3 shows very occasional reactive small T cells (immunohistochemistry, B–F, 100×).
Figure 8
Figure 8
Classic Hodgkin lymphoma (CHL). (A) Lymph node infiltrated by CHL with Hodgkin and Reed-Sternberg cells (HRS cells) in a mixed reactive background composed of eosinophils, small lymphocytes, histiocytes and plasma cells (H&E, 400×). (B) CD30 highlights the HRS cells. (C) The HRS cells are weak PAX5 positive, in contrast to the small reactive B cells, which show strong PAX5 nuclear staining. (D) CD15 is positive in the HRS cells (immunohistochemistry, B–D, 400×). (E) EBERs in-situ hybridization is only positive in HRS cells (400×). Inset: EBV infected cell expresses the EBV-encoded latent membrane protein 1 (LMP1) (immunohistochemistry, 400×).
Figure 9
Figure 9
Chronic active EBV infection, systemic form. (A) Lymph node with preserved architecture (H&E, 25×). (B) Higher magnification demonstrates normal reactive germinal centres (H&E, 200×). (C) EBER in-situ hybridization shows positive cells both in the follicles and in the interfollicular areas (magnification, 200×). (D) Skin biopsy shows a discrete lymphoid infiltrate in the upper dermis and in the sub-epidermis (H&E, 200×). (E) CD3 is positive in the lymphocytes (magnification 200×). (F) Scattered T cell lymphocytes are EBER positive (in-situ hybridization, 200×).
Figure 10
Figure 10
Hydroa vacciniforme-like lymphoproliferative disorder. (A) Sun expose areas of face and arms show papulovesicular eruptions with crusts alternating with varicelliform scars after healing. (B) Skin biopsy with intraepidermal bullae and a dense infiltrate in the dermis surrounding adnexae and blood vessels (H&E, 50×). (C) The lymphoid infiltrate is CD8 positive (magnification 50×). (D) The lymphoid infiltrate is positive for EBV, as demonstrated by in-situ hybridization for EBV-encoded small RNA (EBER) (100×).
Figure 11
Figure 11
Aggressive NK-cell leukaemia. (A) Bone marrow biopsy with a subtle lymphoid infiltrate difficult to identify with H&E stains (H&E, 400×). Insert: EBER in-situ hybridization shows EBER+ cells (400×). (B) Hypercellular bone marrow biopsy with a clear medium-sized cell infiltrate with irregular nuclei (H&E, 400×). (C) The infiltrating cells are CD56 positive. (D) TIA1 is also positive (magnification, C, D, 400×). (E) Liver biopsy with dilated sinuses and a subtle infiltrate of small to medium-sized cells (H&E, 200×). Inset: The cells show atypia with irregular nuclei and one conspicuous nucleolous (H&E, 630×) (F) CD56 is positive in the infiltrating lymphocytes indicative of the NK-cell derivation. (G) EBER in-situ hybridization is positive (magnification, F, G, 200×).
Figure 12
Figure 12
Extranodal, NK/T-cell type, nasal type. (A) Nasal biopsy shows a dense lymphoid infiltrate with extensive ulceration of the epithelium and destruction of adnexae and blood vessels (H&E, 25×). (B) Same biopsy stained with EBER in-situ hybridization reveals the dense EBER+ infiltrate (25×). (C) Medium-sized arteria with angioinvesion and angiodestruction (H&E, 200×). Inset: higher magnification shows the atypical cell infiltrate, with irregular nuclei and abundant cytoplasm (H&E, 630×). (D) The tumour cells are CD56 positive. (E) The cells are EBER positive. (F) TIA1 is also positive in the tumour cells (magnification, D–F, 200×).
Figure 13
Figure 13
Primary EBV+ nodal T cell lymphoma. (A) Lymph node with complete destruction of the normal architecture by a diffuse lymphoid infiltrate (H&E, 100×). (B) Higher magnification shows that the infiltrate is composed of large atypical, pleomorphic cells some resembling Hodgkin and Reed-Stenberg cells (H&E, 400×). (C) Giemsa stain highlights the cytological features of the neoplastic cells (Giemsa, 400×). (D) The tumour cells are CD3 positive. (E) TIA1 is positive. (F) Note the strong, homogeneous expression of CD30. (G) CD56 is positive only in rare malignant cells (immunohistochemistry, D–G, 400×). (H) EBER is positive in the majority of tumour cells (in-situ hybridization, 100×). Inset: LMP1 is positive indicating an EBV latency type II (magnification, 400×).

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