|| Peripheral T cell lymphomas (PTCL) are a heterogeneous group of aggressive neoplasm in adults. Among these are: peripheral T cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T cell lymphoma, extranodal NK/T cell lymphoma (nasal type), enteropathy associated T cell lymphoma, hepatosplenic T cell lymphoma. |
Extranodal natural killer/T-cell lymphoma, nasal type (ENKL), or nasal NK/T cell lymphoma (angiocentric lymphoma), is an aggressive pathology, with predilection for Asian and South American populations (Barrionuevo C et al., 2007; Liang R et al., 2009). Neoplastic cells are surface CD3-, cytoplasmic CD3ε+, CD56+, cytotoxic-molecule positive, Epstein-Barr virus (EBV) positive, with germline T-cell receptor gene (Chan JK et al., 2008). This lymphoma is almost exclusively extranodal (Kwong YL et al., 2005). Occur commonly in the nasal and upper aerodigestive region. Occasional cases present in the skin, salivary gland, testis, and gastrointestinal tract. Quantification of circulating EBV DNA is an accurate biomarker of tumor load (Au WY et al., 2005). Concomitant sequential chemotherapy and radiotherapy is standard treatment. Diagnosis: The diagnosis of ENKL is made based upon the evaluation of a biopsy specimen from the site of involvement, usually in the facial area. Because the morphology of the tumor cells is so variable, it is important to consider this diagnosis in all cases of aggressive extranodal lymphoma associated with vascular invasion and necrosis.
The key diagnostic features are the demonstration of NK/T cell markers and Epstein Barr virus (EBV). Although CD56 is typically expressed, tumors that do not express CD56 may still be classified as ENKL if both cytotoxic molecules and EBV are positive (Chan JK et al., 2008).
Immunophenotype in this case can be useful; these tumors express CD2, cytoplasmic CD3, CD56, and cytotoxic granule proteins (Chan JK et al., 2008).
|Etiology|| Etiology is poorly understood, but is related in part to infection of the tumor cells with Epstein-Barr virus (EBV). Expression of EBV latent membrane protein-1 by immunohistochemistry has also been described (Kanavaros P et al., 1993).|
|Epidemiology|| NK/T-cell lymphomas occur worldwide, with a strong geographic predilection for Asian population (China, Japan, Korea and Southeast Asia) and for Central and South American population (Mexico, Peru, Argentina and Brazil) (Kwong YL et al., 2005). Constituting 5-15% of lymphomas in these countries (Swerdlow SH et al., 2016). |
The median age at presentation is 52 years (Au WY et al., 2009); however, rare cases have been reported in childhood. There is a male predominance with an approximately 2:1 male to female ratio. (Chim SC et al., 2004; Li XY et al., 2009).
|Clinics|| The large majority of patients present with localized disease resulting in symptoms of nasal obstruction, epistaxis, and/or a destructive mass involving the nose, sinuses, or palate (Liu QF et al., 2014). Other extranodal sites may be involved either primarily (extranasal NK/T cell lymphoma) or as a direct extension of the primary tumor. These sites include the upper airway, Waldeyer's ring, gastrointestinal tract, skin, testis, lung, eye, or soft tissue (Tse E et al., 2013). Lymph nodes may be involved secondarily, but are only rarely the primary site of involvement. Bone marrow involvement and B symptoms are seen in approximately 10 and 35 percent of patients, respectively (Li YX et al., 2009). |
|Cytology|| Immunephenotype is similar to that of a NK cell. The atypical cells in most cases express CD2, CD56, and cytoplasmic CD3, but do not express surface CD3. Most cases express cytotoxic granule protein such as granzyme B, TIA-1, and perforin, and lack surface T cell receptor (TCR). Uncommon cases may express CD4, CD8, and/or CD7. (Lei KI et al., 2002).|
|Pathology|| The tumors cells can be of any size, but most commonly are either medium-sized or a mixture of small and large cells. They have a moderate amount of pale/clear cytoplasm with irregularly folded nuclei typically containing granular chromatin and inconspicuous or small nucleoli. Azurophilic granules may be seen on touch preps stained with giemsa (Swerdlow SH et al., 2008).|
|Treatment|| Therapy and prognosis are based upon the stage of the disease. In localized stages, combined modality therapy is the frequent treatment option (i.e., radiotherapy with concurrent chemotherapy) (Tse E et al., 2012). Radiation dose of 50 GY and concurrent therapy with reduced dose 2/3DeVIC (dexamethasone, etoposide, ifosfamide, carboplatin) or VIDL (etoposide, ifosfamide, dexamethasone, L-asparaginase). |
CHOP-based regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) is not recommended for NK/T-cell lymphoma (Kim SJ et al., 2010).
Other chemotherapy regimens like LVP (L-asparaginase, vincristine and prednisolone) or GELOX (gemcitabine, E. coli L-asparaginase, oxaplatin) are been used in this pathology with high rates of remissions.
In disseminated disease cases, SMILE regimen (dexamethasone, methotrexate, ifosfomide, L-asparaginase) achieves best results, but neutropenia occurred in most of the patients with high rates of serious infections (Kwong YL et al., 2012).
The use of hematopoietic stem cell transplantation (HSCT) has been explored in NK/T-cell lymphomas, however most studies contained small number of patients so the results are difficult to interpret.
|Prognosis|| ENKL is an aggressive lymphoma. Without treatment survival is measured in months. The prognosis with treatment is largely related to the location and stage of disease at diagnosis. |
Age over 60 years, stage III/IV disease, distant lymph node involvement, non-nasal type and detectable Epstein-Barr virus viral DNA titer are consider the most important patient information for the prognosis determination.
| Clinicopathologic features and treatment outcome of mature T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classification scheme: a single center experience of 10 years|
| Au WY, Ma SY, Chim CS, Choy C, Loong F, Lie AK, Lam CC, Leung AY, Tse E, Yau CC, Liang R, Kwong YL|
| Ann Oncol 2005 Feb;16(2):206-14|
| Extranodal NK/T-cell lymphoma, nasal type: study of clinicopathologic and prognosis factors in a series of 78 cases from Peru|
| Barrionuevo C, Zaharia M, Martinez MT, Taxa L, Misad O, Moscol A, Sarria G, Guerrero I, Casanova L, Flores C, Zevallos-Giampietri EA|
| Appl Immunohistochem Mol Morphol 2007 Mar;15(1):38-44|
| A role for Blimp1 in the transcriptional network controlling natural killer cell maturation|
| Kallies A, Carotta S, Huntington ND, Bernard NJ, Tarlinton DM, Smyth MJ, Nutt SL|
| Blood 2011 Feb 10;117(6):1869-79|
| Nasal T-cell lymphoma: a clinicopathologic entity associated with peculiar phenotype and with Epstein-Barr virus|
| Kanavaros P, Lescs MC, Brière J, Divine M, Galateau F, Joab I, Bosq J, Farcet JP, Reyes F, Gaulard P|
| Blood 1993 May 15;81(10):2688-95|
| Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses|
| Karube K, Nakagawa M, Tsuzuki S, Takeuchi I, Honma K, Nakashima Y, Shimizu N, Ko YH, Morishima Y, Ohshima K, Nakamura S, Seto M|
| Blood 2011 Sep 22;118(12):3195-204|
| Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma|
| Koo GC, Tan SY, Tang T, Poon SL, Allen GE, Tan L, Chong SC, Ong WS, Tay K, Tao M, Quek R, Loong S, Yeoh KW, Yap SP, Lee KA, Lim LC, Tan D, Goh C, Cutcutache I, Yu W, Ng CC, Rajasegaran V, Heng HL, Gan A, Ong CK, Rozen S, Tan P, Teh BT, Lim ST|
| Cancer Discov 2012 Jul;2(7):591-7|
| Natural killer-cell malignancies: diagnosis and treatment|
| Kwong YL|
| Leukemia 2005 Dec;19(12):2186-94|
| Diagnostic and prognostic implications of circulating cell-free Epstein-Barr virus DNA in natural killer/T-cell lymphoma|
| Lei KI, Chan LY, Chan WY, Johnson PJ, Lo YM|
| Clin Cancer Res 2002 Jan;8(1):29-34|
| Advances in the management and monitoring of extranodal NK/T-cell lymphoma, nasal type|
| Liang R|
| Br J Haematol 2009 Oct;147(1):13-21|
| Angiocentric immunoproliferative lesions: a clinicopathologic spectrum of post-thymic T-cell proliferations|
| Lipford EH Jr, Margolick JB, Longo DL, Fauci AS, Jaffe ES|
| Blood 1988 Nov;72(5):1674-81|
| Immunophenotypic and clinical differences between the nasal and extranasal subtypes of upper aerodigestive tract natural killer/T-cell lymphoma|
| Liu QF, Wang WH, Wang SL, Liu YP, Huang WT, Lu N, Zhou LQ, Ouyang H, Jin J, Li YX|
| Int J Radiat Oncol Biol Phys 2014 Mar 15;88(4):806-13|
| p53 Mutations in nasal natural killer/T-cell lymphoma from Mexico: association with large cell morphology and advanced disease|
| Quintanilla-Martinez L, Kremer M, Keller G, Nathrath M, Gamboa-Dominguez A, Meneses A, Luna-Contreras L, Cabras A, Hoefler H, Mohar A, Fend F|
| Am J Pathol 2001 Dec;159(6):2095-105|
| The 2016 revision of the World Health Organization classification of lymphoid neoplasms|
| Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES|
| Blood 2016 May 19;127(20):2375-90|
| How I treat NK/T-cell lymphomas|
| Tse E, Kwong YL|
| Blood 2013 Jun 20;121(25):4997-5005|