Case 1 -

Introduction to Peripheral T-cell lymphomas and Angioimmunoblastic T-cell Lymphoma Elaine S. Jaffe, M.D National Cancer Institute Bethesda , MD

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Clinical History: The patient is a 60 year old male with fever, skin rash, thrombocytopenia, leukocytosis, and generalized lymphadenopathy. The patient was found to have a monoclonal IgM spike in serum and urine, with plasma cell infiltrates in bone marrow and a presumptive diagnosis of Waldenstrom's macroglobulinemia. The patient was treated with high dose steroids, had transient response and the symptoms recurred. A lymph node biopsy was obtained. Case 1 - Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Classification of T-cell and NK-cell lymphomas Mature T-cell and NK-cell neoplasms are relatively uncommon, accounting for fewer than 10% of all non-Hodgkin's lymphomas (NHL) on a worldwide basis. [1] The most common subtypes of mature T-cell lymphomas are peripheral T-cell lymphoma, unspecified (PTLU) and anaplastic large cell lymphoma (ALCL) (Table 1). [2] Table 1: WHO Classification of Mature T-cell and NK-cell neoplasms Often leukemic or disseminated T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Aggressive NK-cell leukemia Adult T-cell lymphoma/leukemia (HTLV1+) Hepatosplenic T-cell lymphoma Extranodal/ Cutaneous Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Muco-cutaneous gδ T-cell lymphoma (Provisional WHO/EORTC 200547) Mycosis fungoides Sezary syndrome Primary cutaneous anaplastic large cell lymphoma Mainly nodal Peripheral T-cell lymphoma, unspecified Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma (systemic) T-cell and NK-cell lymphomas show significant variations in incidence in different geographical regions and racial populations. For example, T/NK-cell lymphomas comprise a higher proportion of NHL in Asians populations. These differences result from both a true increased incidence, as well as a relative decrease in the frequency of many B-cell lymphomas, such as follicular lymphoma, seen commonly in North America and Europe . HTLV-1 accounts for an increased of adult T-cell leukemia/ lymphoma (ATLL) risk in regions where it is endemic, including southwestern Japan and the Caribbean basin. Another major factor affecting the incidence of T-cell and NK-cell lymphomas is racial predisposition. Extranodal NK-cell lymphomas, nasal-type and aggressive NK-cell leukemia are much more common in Asians than they are in other races. [3] Other groups at increased risk for these EBV-associated diseases are individuals of Native American descent in Central and South America, and Mexico. [4] Other rare EBV-positive lymphomas derived from T-cells showing a similar racial and geographic distribution include fulminant EBV-positive T-cell lymphoproliferative disorder, [5] which has overlapping features with severe chronic active EBV-infection, [6]and Hydroa vacciniforme-like lymphoma, a form of EBV-positive T-cell or NK-cell lymphoma seen mainly in children. [7] Genetic factors linked to defective surveillance of EBV have been postulated to play a role in these epidemiological differences. High viral load at the time of initial viral infection may be an additional risk factor. T-cell lymphomas manifest the immunophenotypic features of post-thymic T lymphocytes, being derived from both aβ T-cells and gδ T-cells. [8] This distinction is based on the structure of the T-cell receptor. Gamma-delta T-cells, along with NK-cells are components of the innate immune system, and do not require antigen sensitization to be active. [9, 10] The innate immune system is functional based only on genes encoded in the host genome. It is distinguished from the adaptive or antigen-specific immune system; most T-cells in peripheral blood and peripheral lymphoid organs belong to the latter. The T-cells of the adaptive immune system are heterogeneous and functionally complex, and include naïve, effector (regulatory and cytotoxic), and memory T-cells. CD4-positive T-cells are primarily regulatory, acting via cytokine production, while CD8-positive (and double negative) T-cells are primarily cytotoxic. Recently much has been learned about a unique T-cell subset found in the normal germinal center. These cells, termed follicular T-helper cells (TFH), provide help to B-cells in the context of the germinal center reaction. They have a unique phenotype, expressing the germinal center-associated markers BCL6 and CD10, normally found on B-cells. TFH express CD4, CD57, produce the chemokines CXCR5 and CXCR13. CXCL13 causes induction and proliferation of follicular dendritic cells, and is involved in B-cell recruitment to the lymph node, by facilitating the adhesion of T-cells to high endothelial venules and allowing them to transit the vessel wall. PTLs show great morphological diversity, and a spectrum of histological appearances can be seen within individual disease entities. The cellular composition can range from small cells with minimal atypia to large cells with anaplastic features. Such a spectrum is seen in ALCL, ATLL, and extranodal NK/T-cell lymphoma, as selected examples. However, cytological atypia does not necessarily correlate with clinical behavior. For these reasons, it has been difficult to apply cytological principles to the classification of PTLs. In a similar vein, immunophenotypic markers have been less useful in classification T-cell lymphomas than B-cell lymphomas, as often one marker is sharing by multiple disease entity. As an example, CD30, a hallmark of ALCL, is found in diverse lymphoid malignancies of T- and B-cell types. Finally, the molecular pathogenesis for most T-cell lymphomas is as yet undiscovered. For the above reasons, clinical features have played a major role in defining many of the specific entities included in the WHO classification. [1] Angioimmunoblastic T-cell lymphoma (AILT) Angioimmunoblastic T-cell lymphoma (AILT) has emerged as a distinctive subtype of PTL with unique pathobiological features. This disease is seen mainly in elderly adults with an equal male : female ratio. Originally thought to be a form of abnormal immune response, most patients present with generalized lymphadenopathy, hepatosplenomegaly, skin rash, and marked constitutional symptoms. Polyclonal hypergammaglobulinemia is an almost constant finding and the lymph nodes usually contain polyclonal plasma cells, as well as frequent large B immunoblasts, despite the absence of well-formed follicles with germinal centers. The neoplastic T-cells have clear cytoplasm, and are distributed in a marked inflammatory background. Other features include prominent arborizing high endothelial venules (HEV) and expansion of dendritic meshworks outside the follicle, usually arising from the prominent HEV. The neoplastic T-cells are CD4-positive T-cells that express CD10 and sometimes BCL6, features that suggested the neoplastic cells might be derived from germinal center based T-cells (TFH). [11] Most recently, two groups have identified increased expression of CXCL13 in AILT, a finding that helps to link together many of these clinical and pathological features. [12, 13] CXCL13 is associated with expansion of follicular dendritic cells, and facilitates the entry of B-cells into the lymph node through their attachment to the HEV, thus helping to clarify the B-cell expansion characteristic of this disease. Another almost constant finding in AILT is the presence of EBV-positive B-cells. It has been postulated that this finding is secondary to decreased immune surveillance and reactivation of EBV in the setting of a compromised immune system. [14] However, EBV-positive B-cells are found even very early in the course of the disease. In some cases this phenomenon progresses to an EBV-positive B-cell lymphoproliferative disorder resembling post-transplant polymorphic B-cell lymphoma. In other instances the EBV-positive B-cells may resemble Reed-Sternberg cells, leading to an erroneous diagnosis of classical Hodgkin's lymphoma. [15] References Jaffe ES, Harris NL, Stein H, Vardiman J. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001. Savage KJ, Chhanabhai M, Gascoyne RD, Connors JM. Characterization of peripheral T-cell lymphomas in a single North American institution by the WHO classification. Ann Oncol 2004;15(10):1467-75. Nava VE, Jaffe ES. The Pathology of NK-Cell Lymphomas and Leukemias. Adv Anat Pathol 2005;12(1):27-34. Elenitoba-Johnson KSJ, Zarate-Osorno A, Meneses A, et al. Cytotoxic granular protein expression, Epstein-Barr virus strain type, and latent membrane protein-1 oncogene deletions in nasal T-lymphocyte/natural killer cell lymphomas from Mexico. Mod Pathol 1998;11(8):754-61. Quintanilla-Martinez L, Kumar S, Fend F, et al. Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome. Blood 2000;96(2):443-51. Kimura H, Hoshino Y, Kanegane H, et al. Clinical and virologic characteristics of chronic active Epstein-Barr virus infection. Blood 2001;98(2):280-6. Zhang Y, Nagata H, Ikeuchi T, et al. Common cytological and cytogenetic features of Epstein-Barr virus (EBV)-positive natural killer (NK) cells and cell lines derived from patients with nasal T/NK-cell lymphomas, chronic active EBV infection and hydroa vacciniforme-like eruptions. British Journal of Haematology 2003;121(5):805-14. Delves PJ, Roitt IM. The Immune System. First of two parts. N Engl J Med 2000;343:37-49. Krenacs L, Smyth MJ, Bagdi E, et al. The serine protease granzyme M is preferentially expressed in NK-cell, gδ T-cell, and intestinal T-cell lymphomas: evidence of origin from lymphocytes involved in innate immunity. Blood 2003;101(9):3590-3. Jaffe ES, Krenacs L, Raffeld M. Classification of cytotoxic T-cell and natural killer cell lymphomas. Semin Hematol 2003;40(3):175-84. Attygalle A, Al-Jehani R, Diss TC, et al. Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10. Blood 2002;99(2):627-33. Dupuis J, Boye K, Martin N, et al. Expression of CXCL13 by neoplastic cells in angioimmunoblastic T-cell lymphoma (AITL): a new diagnostic marker providing evidence that AITL derives from follicular helper T cells. Am J Surg Pathol 2006;30(4):490-4. Grogg KL, Attygalle AD, Macon WR, Remstein ED, Kurtin PJ, Dogan A. Angioimmunoblastic T-cell lymphoma: a neoplasm of germinal-center T-helper cells? Blood 2005;106(4):1501-2. Weiss LM, Jaffe ES, Liu XF, Chen YY, Shibata D, Medeiros LJ. Detection and localization of Epstein-Barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma. Blood 1992;79(7):1789-95. Quintanilla-Martinez L, Fend F, Moguel LR, et al. Peripheral T-cell lymphoma with Reed-Sternberg-like cells of B-cell phenotype and genotype associated with Epstein-Barr virus infection. Am J Surg Pathol 1999;23(10):1233-40.