{"id":344,"date":"2009-09-01T00:36:51","date_gmt":"2009-09-01T05:36:51","guid":{"rendered":"http:\/\/www.cttr.org\/cms\/?p=344"},"modified":"2009-09-19T19:20:22","modified_gmt":"2009-09-20T00:20:22","slug":"september-2009-a-previously-healthy-80-y-o-male-with-right-axillary-lymphadenopathy","status":"publish","type":"post","link":"https:\/\/www.cttr.org\/cms\/?p=344","title":{"rendered":"September 2009: A previously healthy 80 y.o. male with right axillary lymphadenopathy"},"content":{"rendered":"

\"\"History:<\/strong> A previously healthy 80 year-old man presented with a one-month history of right axillary lymphadenopathy.\u00c2\u00a0 Physical examination revealed a mildly tender, firm, two cm lymph node in the right axilla.\u00c2\u00a0 No other lesions identified.<\/p>\n

Imaging studies confirmed the presence of an enlarged lymph node in the right axilla.\u00c2\u00a0 There were no other radiological abnormalities.<\/p>\n

Microscopic sections revealed complete effacement of lymph node architecture by a polymorphous lymphoid infiltrate consisting of large atypical lymphoid cells with open chromatin, prominent nucleoli, and moderate amounts of cytoplasm against a background of predominately small lymphocytes (Figs. 1<\/a>,2<\/a>,3<\/a>).\u00c2\u00a0 Large atypical lymphoid cells were positive for CD20 and CD79a, while the smaller background lymphocytes were CD3, CD5 and PAX5 positive (Fig. 4<\/a>).\u00c2\u00a0 Epstein-Barr virus genomes were detected in the large atypical lymphoid cells by EBER in situ hybridization.<\/p>\n

Diagnosis:<\/strong> \u00e2\u20ac\u0153EBV positive diffuse large B-cell lymphoma of the elderly\u00e2\u20ac\u009d<\/p>\n

Hannah Wong MD, Jun Wang MD, Donald Chase MD
\nDepartment of Pathology, Loma Linda University and Medical Center, Loma
\nLinda, California
\nCalifornia Tumor Tissue Registry, Loma Linda, California<\/p>\n

Discussion:<\/strong> EBV positive diffuse large B-cell lymphoma of the elderly (EBV+ DLBCL, aka “age-related EBV-associated lymphoproliferative disorder”), is a rare B-cell lymphoproliferative disorder that occurs in elderly patients with no known history of immunodeficiency or lymphoma.\u00c2\u00a0 The entity was first described by Oyama et al. in 2003 and was added as a distinct entity in the newly published WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.<\/p>\n

As the name suggests, EBV+ DLBCL of the elderly is a disease affecting patients over the age of 50 years.\u00c2\u00a0 There is a slight male predominance of 1.4:1.\u00c2\u00a0 Typically there is no history of immunodeficiency or lymphoma.\u00c2\u00a0 Presentation symptoms and signs include fever, night sweats, weight loss and lymphadenopathy.\u00c2\u00a0 Extranodal sites found at presentation include skin, lung, tonsil and stomach.<\/p>\n

Histologically, the nodal or native tissue architecture is completely effaced by large atypical lymphoid cells\/immunoblasts as well as Reed-Sternberg-like giant cells.\u00c2\u00a0 Accompanying these elements are variable numbers of small lymphocytes, plasma cells, histiocytes, centroblasts and immunoblasts.\u00c2\u00a0 Although EBV+ DLBCL of the elderly was originally separated into two subtypes; polymorphic lymphoproliferative disorder (PLPD) and large cell lymphoma (LCL) recent studies have shown the sub-classification to be clinically irrelevant.<\/p>\n

The neoplastic large lymphoid cells show expression of pan-B cell markers (CD20, CD79a and PAX5), with variable expression of CD30, LMP-1 and EBNA-2.\u00c2\u00a0 Light chain restriction may be present but has been difficult to demonstrate in most cases. CD15, CD10 and Bcl-6 are generally negative.\u00c2\u00a0 Neoplastic cells showing EBER positivity and Ki-67 expression is generally high.<\/p>\n

Differential diagnoses of EBV+ DLBCL of the elderly include other B-cell lymphoproliferative disorders such as Burkitt lymphoma, post-transplant lymphoproliferative disorder (PTLD), HIV-associated lymphoproliferative disorder, EBV- DLBCL, and EBV+ classical Hodgkin lymphoma (cHL).\u00c2\u00a0 It is important to differentiate these entities in order to provide the most targeted and effective treatment for the patients.<\/p>\n

\u00e2\u20ac\u00a2\u00c2\u00a0\u00c2\u00a0 \u00c2\u00a0Burkitt lymphoma (BL) is a highly aggressive lymphoma with three clinical variants:<\/p>\n

    \n
  1. Endemic type mostly occurs in children between the ages of 4 – 7 in equatorial Africa.<\/li>\n
  2. Sporadic type\u00c2\u00a0 is more common in the United States and Western Europe, where the median age is 30 years.<\/li>\n
  3. Immunodeficiency-associated BL patients are virtually all immunocompromised, mostly due to HIV infection.<\/li>\n<\/ol>\n

    BL has a variable degree of EBV involvement with endemic types having the highest association.\u00c2\u00a0 Although the morphology of BL varies slightly in each type, the most common pattern is of medium-sized cells in a diffuse monotonous pattern with multiple benign macrophages having ingested apoptotic tumor cells resulting in the classic \u00e2\u20ac\u0153starry-sky\u00e2\u20ac\u009d pattern.\u00c2\u00a0 Multiple mitotic figures may be present.\u00c2\u00a0 Immunohistochemical stains can be helpful in differentiating BL from EBV+ DLBCL of the elderly since the malignant cells in BL are usually CD10 and BCL-6 positive while the malignant cells of EBV+ DLBCL are negative for those two markers.\u00c2\u00a0 BL is also unique in that t(8;22) involving the c-myc oncogene is a constant feature; however this translocation has not been investigated in EBV+ DLBCL of the elderly.<\/p>\n

    \u00e2\u20ac\u00a2\u00c2\u00a0\u00c2\u00a0 \u00c2\u00a0Post-transplant lymphoproliferative disorder (PTLD) is a lymphoid proliferation that arises in immunosuppressed recipients usually involving a solid organ or bone marrow allograft.\u00c2\u00a0 EBV has been found to be the driving force in PTLD, leading to early polyclonal proliferations and ultimately the development of lymphomas.\u00c2\u00a0 Four morphologic categories of PTLD are:<\/p>\n

      \n
    1. Early lesions resemble reactive hyperplasia and\/or infectious mononucleosis. These lesions show an expanded paracortex filled with plasma cells and immunoblasts with a background of small T-cells with partial preservation of the underlying normal tissue architecture.<\/li>\n
    2. Polymorphic PTLD shows effacement of the normal nodal\/extranodal architecture by a mixture of large immunoblasts and plasma cells with smaller lymphocytes.\u00c2\u00a0 Necrosis, mitoses and atypical immunoblasts may also be present.<\/li>\n
    3. Monomorphic PTLD has a monomorphic infiltrate effacing nodal\/extranodal tissues with confluent sheets of atypical B-cells or plasma cells.
      \nThe Hodgkin lymphoma (HL) variant is similar in morphology and immunophenotype to classical Hodgkin lymphoma.\u00c2\u00a0 It displays Reed-Sternberg (HRS)-like cells and variants, and are positive for CD30 and CD15, but not CD20.<\/li>\n<\/ol>\n

      Despite splitting PTLD variants into four morphologies, the distinction is of limited value.\u00c2\u00a0 The clinical history currently appears to be the most helpful criterion for differentiating PTLD from EBV+ DLBCL of the elderly.<\/p>\n

      \u00e2\u20ac\u00a2\u00c2\u00a0\u00c2\u00a0 \u00c2\u00a0HIV-related lymphomas display EBV presence about 60% of the time.\u00c2\u00a0 They are generally aggressive B-cell lymphomas related to other lymphoproliferative disorders which are associated with HIV infection such as BL, DLBCL, primary effusion lymphoma, plasmablastic lymphoma of the oral cavity and others.\u00c2\u00a0 Interestingly, other viruses such as Kaposi\u00e2\u20ac\u2122s sarcoma-associated herpes virus\/human herpes virus 8 (KSHV\/HHV8) have also been found in several categories of immunodeficiency-associated lymphoma.\u00c2\u00a0 But despite the similar morphological and immunohistochemical features of HIV- associated LPD and EBV+ DLBCL of the elderly, a positive HIV serology usually separates the two.<\/p>\n

      \u00e2\u20ac\u00a2\u00c2\u00a0\u00c2\u00a0 \u00c2\u00a0EBV+ classical Hodgkin lymphoma (cHL).\u00c2\u00a0 Classical Hodgkin lymphoma accounts for 95% of all Hodgkin lymphomas.\u00c2\u00a0 cHL has a bimodal age distribution with the first peak at 15 to 35 years and a second peak later in life.\u00c2\u00a0 Approximately 30-50% of cHL have been found to be EBV positive.\u00c2\u00a0 Patients with EBV+ cHL have a more aggressive clinical course and worse prognosis in comparison to those with EBV- cHL.\u00c2\u00a0 Morphologically, EBV+ cHL has the classic morphology of cHL with HRS cells in a background of inflammatory cells.\u00c2\u00a0 The large HRS cells have abundant cytoplasm and at least two large round nuclei with prominent nucleoli.\u00c2\u00a0 These HRS cells are positive for CD30 and mostly positive for CD15 but are negative for CD45.\u00c2\u00a0 This is in comparison to EBV+ DLBCL of the elderly which is usually positive for CD45, CD20\/CD79a, variably positive for CD30 but negative for CD15.\u00c2\u00a0 EBER has been found to be positive in the neoplastic cells of EBV+ DLBCL of the elderly more often than in the neoplastic HRS cells and their variants of EBV+ cHL.\u00c2\u00a0 Thus, immunohistochemical studies and EBER are the most useful tools to distinguish EBV+ cHL from EBV+ DLBCL of the elderly.<\/p>\n

      \u00e2\u20ac\u00a2\u00c2\u00a0\u00c2\u00a0 \u00c2\u00a0EBV- DLBCL is virtually the same as EBV+ DLBCL of the elderly except that it may occur in patients of any age and is not EBV+.\u00c2\u00a0 Morphologically, these two entities are virtually indistinguishable.\u00c2\u00a0 However, EBER positivity would help separate it from the EBV+ DLBCL of the elderly.<\/p>\n

      EBV+ DLBCL of the elderly has a highly aggressive behavior; the median survival for this disease is approximately two years.\u00c2\u00a0 Patients with EBV+ DLBCL of the elderly have been found to be less responsive to the standard chemotherapy regimens for large B-cell lymphoma compared with other forms of B-cell lymphoproliferative disorders.<\/p>\n

      Suggested reading:<\/strong><\/p>\n

      1.\u00c2\u00a0\u00c2\u00a0 \u00c2\u00a0Nakamura S, Jaffe E.S, Swerdlow S.H.EBV+ Diffuse large B-cell of the elderly.. In: Swerdlow S.H., Campo E., Harris N.L., Jaffe E.S., Pileri S.A., Stein H., Thiele J., Vardiman J.W. (Eds.): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC: Lyon, 243-244 2008.
      \n2.\u00c2\u00a0\u00c2\u00a0 \u00c2\u00a0Shimoyama Y., Yamamoto K., Asano N., Oyama T., Kinoshita T., Nakamura S. Age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorders: Special references in lymphomas surrounding this newly recognized clinicopathologic disease.\u00c2\u00a0 Cancer Sci\u00c2\u00a0 9:1085-1091, 2008.
      \n3.\u00c2\u00a0\u00c2\u00a0 \u00c2\u00a0Shimoyama Y., Oyama T., Asano Net al. Senile Epstein-barr virus-associated B-cell lymphoproliferative disorders: a mini review. J Clin Exp Hematopathol\u00c2\u00a0 46:1-4, 2006.
      \n4.\u00c2\u00a0\u00c2\u00a0 \u00c2\u00a0Oyama T., Ichimura K., Suzuki R., et al . Senile EBV+ B-cell lymphoproliferative disorders: a clinicopathologic study of 22 patients. Am J Surg Pathol\u00c2\u00a0 27;16-26. 2003.
      \n5.\u00c2\u00a0\u00c2\u00a0 \u00c2\u00a0Mueller S., Aigner T., Haag J., Schwartz R., Niedobitek G. Senile EBV-associated B-cell lymphoproliferative disorder of prepatellar bursa in elderly patient with multifocal urate arthropathy. Hematol Oncol\u00c2\u00a0 25:140-142, 2007.
      \n6.\u00c2\u00a0\u00c2\u00a0 \u00c2\u00a0Oyama T., Yamamoto K., Asano N., et al . Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: A study of 96 patients. Clin Cancer Res\u00c2\u00a0 13:5124-5132,\u00c2\u00a0 2007.<\/p>\n","protected":false},"excerpt":{"rendered":"

      History: A previously healthy 80 year-old man presented with a one-month history of right axillary lymphadenopathy.\u00c2\u00a0 Physical examination revealed a mildly tender, firm, two cm lymph node in the right axilla.\u00c2\u00a0 No other lesions identified. Imaging studies confirmed the presence of an enlarged lymph node in the right axilla.\u00c2\u00a0 There were no other radiological abnormalities. […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/www.cttr.org\/cms\/index.php?rest_route=\/wp\/v2\/posts\/344"}],"collection":[{"href":"https:\/\/www.cttr.org\/cms\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.cttr.org\/cms\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.cttr.org\/cms\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.cttr.org\/cms\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=344"}],"version-history":[{"count":14,"href":"https:\/\/www.cttr.org\/cms\/index.php?rest_route=\/wp\/v2\/posts\/344\/revisions"}],"predecessor-version":[{"id":408,"href":"https:\/\/www.cttr.org\/cms\/index.php?rest_route=\/wp\/v2\/posts\/344\/revisions\/408"}],"wp:attachment":[{"href":"https:\/\/www.cttr.org\/cms\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=344"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.cttr.org\/cms\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=344"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.cttr.org\/cms\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=344"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}