The Epstein-Barr virus (EBV) is a member of the herpes family of viruses and is very common in humans. EBV is most often associated with infectious mononucleosis. However, it is estimated that 1% of tumors including lymphoproliferative, epithelial and mesenchymal are linked to EBV infection. EBV has a tropism for certain epithelial cells, lymphocytes and myocytes. Like other herpesviruses, EBV has both lytic and latent phases of infection. In the latent form, EBV-encoded genes ensure the survival of the viral genome, allowing it to circumvent the host’s immune surveillance by limited expression of viral proteins and carries with it the risk of neoplastic transformation. Cytologists are likely to encounter EBV-associated malignancies in cytology material but unlike other herpesviruses, EBV does not evoke a viral cytopathic effect. The manifestation of EBV-related tumors is also often variable depending upon the patient’s immune status. Therefore, knowledge of the patient’s EBV status and immune competence (e.g. HIV-infection or transplant-related immunosuppression) combined with the cytomorphology and results of ancillary studies are often all required to make a diagnosis of EBV-associated malignancy. This review discusses the unique cytomorphology and ancillary studies required to diagnose EBV-related neoplasms.

1.
Unger E, Purtilo DT: Epstein-Barr virus and human diseases; in Connor DH, Chandler FW, Manz HJ, et al (eds): Pathology of Infectious Diseases. Stamford, Appleton & Lange, 1997, vol 1, pp 113–123.
2.
Johannsen EC, Kaye KM: Epstein-Barr virus (infectious mononucleosis, Epstein-Barr virus-associated malignant diseases, and other diseases); in Mandell GL, Bennett JE, Dolin R (eds): Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, ed 7. Philadelphia, Elsevier, 2010, pp 1989–2010.
3.
Parkin D: The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006;118:3030–3044.
4.
Carbone A, Gloghini A, Dotti G: EBV-associated lymphoproliferative disorders: classification and treatment. Oncologist 2008;13:577–585.
5.
Rezk S, Weiss L: Epstein-Barr virus-associated lymphoproliferative disorders. Hum Pathol 2007;38:1293–1304.
6.
Delecluse H, Feederle R, O’Sullivan B, Taniere P: Epstein-Barr virus-associated tumors: an update for the attention of the working pathologist. J Clin Pathol 2007;60:1358–1364.
7.
Gulley M, Tang W: Laboratory assays for Epstein-Barr related disease. J Mol Diagn 2008;10:279–292.
8.
Naresh K: Lymphoproliferative disorders in the immunosuppressed. Diagn Histopathol 2009;16:206–215.
9.
Tran H, Nourse J, Hall S, Green M, Griffiths L, Gandhi M: Immunodeficiency-associated lymphomas. Blood Rev 2008;22:261–281.
10.
Hecht J, Cibas E, Kutok J: Fine-needle aspiration cytology of lymphoproliferative disorders in the immunosuppressed patient: the diagnostic utility of is situ hybridization for Epstein-Barr virus. Diagn Cytopathol 2002;26:360–365.
11.
Epstein MA, Achong BG, Barr YM: Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet 1964;:702–703.
12.
Pantanowitz L, Leiman G, Garcia L: Microbiology; in Pantanowitz L, Michelow P, Khalbuss WE (eds): Cytopathology of Infectious Diseases. New York, Springer, in press.
13.
Gulley ML, Glaser SL, Craig FE, Borowitz M, Mann RB, Shema SJ, Ambinder RF: Guidelines for interpreting EBER in situ hybridization and LMP1 immunohistochemical tests for detecting Epstein-Barr virus in Hodgkin lymphoma. Am J Clin Pathol 2002;117:259–267.
14.
Cohen JI: Epstein-Barr virus infection. N Engl J Med 2000;343:481–492.
15.
Thorley-Lawson DA, Gross A: Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 2004;350:1328–1337.
16.
Das DK, Francis IM, Sharma PN, Sathar SA, John B, George SS, Mallik MK, Sheikh ZA, Haji BE, Pathan SK, Madda JP, Mirza K, Ahmed MS, Junaid TA: Hodgkin’s lymphoma: diagnostic difficulties in fine-needle aspiration cytology. Diagn Cytopathol 2009;37:564–573.
17.
Cibas E, Ducatman B (eds): Cytology: Diagnostic Principles and Clinical Correlates, ed 3. Philadelphia, Saunders Elsevier, 2009.
18.
Sidawy M, Syed A (eds): Fine Needle Aspiration Cytology. Philadelphia, Churchill Livingstone Elsevier, 2007.
19.
Iacobuzio-Donahue CA, Clark DP, Ali SZ: Reed-Sternberg-like cells in lymph node aspirates in the absence of Hodgkin’s disease: pathologic significance and differential diagnosis. Diagn Cytopathol 2002;27:335–339.
20.
Walts AE: Fine-needle aspiration of extranodal Hodgkin’s lymphoma misinterpreted as carcinoma. Diagn Cytopathol 2009;37:313–314.
21.
Kolonić SO, Prasek-Kudrna K, Roso V, Radić-Kristo D, Planinc-Peraica A, Dzebro S, Kardum-Skelin I, Jaksić B: Value of fine-needle aspiration cytology in diagnosis of Hodgkin’s lymphoma and anaplastic large cell lymphoma: one centre experience. Coll Antropol 2010;34:75–79.
22.
Stelow EB, Policarpio-Nicolas ML, Sudduth KW, LeGallo RD: Burkitt lymphoma. Diagn Cytopathol 2008;36:172–173.
23.
Troxell ML, Bangs CD, Cherry AM, Natkunam Y, Kong CS: Cytologic diagnosis of Burkitt lymphoma. Cancer 2005;105:310–318.
24.
Slack GW, Gascoyne RD: MYC and aggressive B-cell lymphomas. Adv Anat Pathol 2011;18:219–228.
25.
Ali AE, Morgen EK, Geddie WR, Boerner SL, Massey C, Bailey DJ, da Cunha Santos G: Classifying B-cell non-Hodgkin lymphoma by using MIB-1 proliferative index in fine-needle aspirates. Cancer Cytopathol 2010;118:166–172.
26.
Adam P, Bonzheim I, Fend F, Quintanilla-Martínez L: Epstein-Barr virus-positive diffuse large B-cell lymphomas of the elderly. Adv Anat Pathol 2011;18:349–355.
27.
Shimoyama Y, Asano N, Kojima M, Morishima S, Yamamoto K, Oyama T, et al: Age-related EBV-associated B-cell lymphoproliferative disorders: diagnostic approach to a newly recognised clinicopathologic entity. Pathol Int 2009;59:835–843.
28.
Shimoyama Y, Yamamoto K, Asano N, Oyama T, Kinoshita T, Nakamura S: Age-related Epstein-Barr virus associated B-cell lymphoproliferative disorders: special reference to lymphomas surrounding this newly recognised clinicopathologic disease. Cancer Sci 2008;99:1085–1091.
29.
Pantanowitz L, Carbone A, Dezube BJ: Historical perspective of plasmablastic lymphoma; in Castillo JJ (ed): Plasmablastic Lymphoma. An Emergent Disease with Poor Prognosis. Saarbrücken, VDM Verlag Dr. Muller, 2010, pp 3–15.
30.
Pantanowitz L, Dezube BJ: Editorial comment: plasmablastic lymphoma – a diagnostic and therapeutic puzzle. AIDS Read 2007;17:448–449.
31.
Castillo J, Pantanowitz L, Dezube BJ: HIV-associated plasmablastic lymphoma: lessons learned from 112 published cases. Am J Hematol 2008;83:804–809.
32.
Lin O, Gerhard R, Zerbini MC, Teruya-Feldstein J: Cytologic features of plasmablastic lymphoma. Cancer 2005;105:139–144.
33.
Pantanowitz L, Pihan G, Carbone A, Dezube BJ: Differentiating HIV-associated non-Hodgkin’s lymphomas with similar plasmacellular differentiation. J HIV Ther 2009;14:24–33.
34.
Wang J, Hernandez O, Sen F: Plasmablastic lymphoma involving breast: a case diagnosed by fine-needle aspiration and core needle biopsy. Acta Cytopathol 2008;36:257–261.
35.
Raviele P, Pruneri G, Maiorano E: Plasmablastic lymphoma: a review. Oral Dis 2009;15:38–45.
36.
Skoog L, Tani E: FNA cytology in the diagnosis of lymphoma; in SR Orell (ed): Monographs in Clinical Cytology. Basel, Karger, 2009.
37.
Mack AA, Sugden B: EBV is necessary for proliferation of dually infected primary effusion lymphoma cells. Cancer Res 2008;68:6963–6968.
38.
Brimo F, Popradi G, Michel RP, Auger M: Primary effusion lymphoma involving three body cavities. Cytojournal 2009;6:21.
39.
Moatamed NA, Song SX, Apple SK, Said JW: Primary effusion lymphoma involving the cerebrospinal fluid. Diagn Cytopathol 2011, E-pub ahead of print.
40.
Lang TU, Khalbuss WE, Monaco SE, Michelow P, Pantanowitz L: review of HIV-related cytopathology. Patholog Res Int 2011;2011:256083.
41.
Afessa B: Pleural effusions and pneumothoraces in AIDS. Curr Opin Pulm Med 2001;7:202–209.
42.
Sullivan R, Pantanowitz L, Casper C, Stebbing J, Dezube B: Epidemiology, pathophysiology and treatment of Kaposi sarcoma- associated herpes-virus disease: Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease. Clin Infect Dis 2008;47:1209–1215.
43.
Patel M, Michelow P, Philip V, Patel P, Ameen O, Allard U, Heard V: AIDS-related primary effusion of the pleural cavity: a case report. South Afr J Epidemiol Infect 1999;14:49–51.
44.
Aboulafia DM, Pantanowitz L, Dezube BJ: AIDS-related non-Hodgkin lymphoma: still a problem in the era of HAART. AIDS Read 2004;14:605–617.
45.
Gerstner E, Batchelor T: Primary nervous system lymphoma. Arch Neurol 2010;67:291–297.
46.
Ohori NP, Whisnant RE, Nalesnik MA, Swerdlow SH: Primary pleural effusion posttransplant lymphoproliferative disorder: distinction from secondary involvement and effusion lymphoma. Diagn Cytopathol 2001;25:50–53.
47.
Davey DD, Gulley ML, Walker WP, Zaleski S: Cytologic findings in posttransplant lymphoproliferative disease. Acta Cytol 1990;34:304–310.
48.
Dusenbery D, Nalesnik MA, Locker J, Swerdlow SH: Cytologic features of post-transplant lymphoproliferative disorder. Diagn Cytopathol1997;16:489–496.
49.
Swerdlow SH, Webber SA, Chadburn A, Ferry JA: Post-transplant lymphoproliferative disorder; in Swerdlow SH, Campo E, Harries NL, et al (eds): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC, 2008, pp 343–349.
50.
Ng WK, Lee CY, Li AS, Cheung LK: Nodal presentation of nasal-type NK/T-cell lymphoma: report of two cases with fine needle aspiration cytology findings. Acta Cytol 2003;47:1063–1068.
51.
Cho EY, Gong G, Khang SK, Kang YK, Huh J: Fine needle aspiration cytology of CD56-positive natural killer/T-cell lymphoma of soft tissue. Cancer 2002;96:344–350.
52.
Kishimoto K, Kitamura T, Hirayama Y, Tate G, Mitsuya T: Three cases of extranodal NK/T-cell lymphoma of the nasal type diagnosed by nasal brush cytology. Diagn Cytopathol 2007;35:125–129.
53.
Gerstner E, Batchelor T: Primary nervous system lymphoma. Arch Neurol 2010;67:291–297.
54.
Galindo L, Garcia F, Hanau C, Lessin S, Jhala N, Bigler R, et al: Fine needle aspiration biopsy in the evaluation of lymphadenopathy associated with cutaneous T-cell lymphoma (mycosis fungoides/ Sezary syndrome). Am J Clin Pathol 2000;113:865–871.
55.
Williams WL, Clark DA, Saiers JH: Fine needle aspiration diagnosis of lymphomatoid granulomatosis: a case report. Acta Cytol 1992;36:91–94.
56.
Vargas J, Arguelles M, Nevado M, de la Serna J, de Agustín P: Fine needle aspiration biopsy of a cutaneous relapse of lymphomatoid granulomatosis: a case report. Acta Cytol 1993;37:205–208.
57.
Deyrup A: Epstein-Barr virus-associated epithelial and mesenchymal neoplasms. Human Pathol 2008;39:473–483.
58.
Chang AR, Liang XM, Chan AT, et al: The use of brush cytology and directed biopsies for the detection of nasopharyngeal carcinoma and precursor lesions. Head Neck 2001;23:637–645.
59.
Chan JKC, Bray F, McCarron P, et al: Nasopharyngeal carcinoma; in Barnes L, Eveson JW, Reichart P, Sidransky D (eds): World Health Organization Classification of Tumours – Pathology and Genetics of Head and Neck Tumours. Lyon, IARC Press, 2005, pp 85–97.
60.
Brennan B: Nasopharyngeal carcinoma. Orphanet J Rare Dis 2006;1:23.
61.
Kollur S, El Haq I: Fine-needle aspiration cytology of metastatic nasopharyngeal carcinoma in cervical lymph nodes: comparison with metastatic squamous-cell carcinoma, and Hodgkin’s and non-Hodgkin’s lymphoma. Diagn Cytopathol 2003;28:18–22.
62.
Orell S, Sterret G, Whitaker D: Fine Needle Aspiration Cytology, ed 4. Philadelphia, Elsevier Churchill Livingstone, 2005.
63.
Hanji D, Shujing S, Shuwei H, Gohao L: The cytological diagnosis of nasopharyngeal carcinoma from exfoliated cells collected by suction method. An eight-year experience. J Laryngol Otol 1983;97:727–734.
64.
Wan SK, Chan JK, Lau WH, Yip TT: Basaloid-squamous carcinoma of the nasopharynx. An Epstein-Barr virus-associated neoplasm compared with morphologically identical tumors occurring in other sites. Cancer 1995;76:1689–1693.
65.
Banks ER, Frierson HF Jr, Covell JL: Fine needle aspiration cytologic findings in metastatic basaloid squamous cell carcinoma of the head and neck. Acta Cytol 1992;36:126–131.
66.
Gilcrease MZ, Guzman-Paz M: Fine-needle aspiration of basaloid squamous carcinoma: a case report with review of differential diagnostic considerations. Diagn Cytopathol 1998;19:210–215.
67.
Smith SS, Fowler LJ, Hausenfluke L, Cho CG, Eagan PA, Gulley ML: Diagnosis of Epstein-Barr virus associated nasopharyngeal carcinoma using fine-needle aspiration biopsy and molecular diagnostics. Diagn Cytopathol 1995;13:155–159.
68.
Pattle S, Farrell P: The role of Epstein-Barr virus in cancer. Expert Opin Biol Ther 2006;6:1193–1205.
69.
Shah K, Young L: Epstein-Barr virus and carcinogenesis: beyond Burkitt’s lymphoma. Clin Microbiol Infect 2009;15:982–988.
70.
Uozaki H, Fukayama M: Epstein-Barr virus and gastric carcinoma. Int J Clin Exp Pathol 2008;1:198–216.
71.
Fukayama M, Hino R, Uozaki H: Epstein-Barr virus and gastric carcinoma: virus-host interactions leading to carcinoma. Cancer Sci 2008;99:1726–1733.
72.
Purgina B, Rao U, Miettinen M, Pantanowitz L: AIDS-related EBV-associated smooth muscle tumors: a review of 64 published cases. Patholog Res Int 2011;10:561548.
73.
Pantanowitz L, Kuperman M, Goulart R: Clinical history of HIV infection may be misleading in cytopathology. Cytojournal 2010;7:7.
74.
Deyrup A, Lee V, Hill C, Cheuk W, Toh H, Kesavan S, et al: Epstein-Barr virus-associated smooth muscle tumors are distinctive mesenchymal tumors reflecting multiple infection events: a clinicopathologic and molecular analysis of 29 tumors from 19 patients. Am J Surg Pathol 2006;30:75–82.
75.
Lee ES, Locker J, Nalesnik M, Reyes J, Jaffe R, Alashari M, Nour B, Tzakis A, Dickman PS: The association of Epstein-Barr virus with smooth-muscle tumors occurring after organ transplantation. N Engl J Med 1995;332:19–25.
76.
Wright C, Nayler S, Leiman G: Cytopathology of follicular dendritic cell tumors. Diagn Cytopathol 1997;17:138–142.
77.
Guiter G, Sanchez-Marull R, Sapia S, Zakowski M, Gamboni M: Fine-needle aspiration of a follicular dendritic-cell tumor: report of a case and review of the literature. Diagn Cytopathol 2000;22:238–242.
78.
Lau P, Wong O, Liu P, Cheung O, Cheung L, Wong W, et al: Myopericytoma in patients with AIDS: a new class of Epstein-Barr virus-associated tumor. Am J Surg Pathol 2009;33:1666–1672.
79.
Dray M, McCarthy S, Palmer A, Bonar S, Stalley P, Marioniemi V, et al: Myopericytoma: a unifying term for a spectrum of tumours that show overlapping features with myofibroma. A review of 14 cases. J Clin Pathol 2006;59:67–73.
80.
Rho B, Lee S, Kwon S: Myopericytoma of the neck: sonographic appearance and sonographically guided needle biopsy. J Clin Ultrasound, 2011;39:469–472.
81.
Comito MA, Sun Q, Lucas KG: Immunotherapy for Epstein-Barr virus-associated tumors. Leuk Lymphoma 2004;45:1981–1987.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.