You are here
Pathobiology of Epstein–Barr virus–driven peripheral T-cell lymphomas
Seminars in Diagnostic Pathology, 3, 28, pages 234 - 244
In the present review, the authors described the pathobiological features of Epstein–Barr virus (EBV)–driven T/natural killer cell–derived malignancies. These rare tumors appear to be quite heterogeneous with regard to both clinical and pathologic features. Nonetheless, some elements, especially regarding the possible role of EBV (ie, genomic predisposition, pathogenesis, pattern of latency), are similar, enforcing the concept of a causative role for the virus. In clinical practice, although definitely rare in Western countries, the tumors are not exceptional; thus, they should be taken into account in the differential diagnosis of T-lymphoproliferative disorders, also considering the need for extremely prompt intervention. The prognosis of such tumors is generally poor using current approaches. A better understanding of their molecular pathogenesis may lead to significant therapeutic improvements. For example, the nuclear factor-κB pathway and platelet-derived growth factor receptor inhibition may represent 2 options to be tested in clinical trials.
Keywords: Peripheral T-cell lymphomas, EBV, Natural killer, T/NK lymphoproliferative disorder.
The Epstein–Barr virus (EBV), also called human herpesvirus 4, belongs to the herpes family and is one of the most common viruses in humans. EBV commonly causes either asymptomatic infections or infectious mononucleosis. In addition, it has been related to the development of certain cancer types, 1 including lymphoproliferative disorder and carcinomas. In particular, EBV was originally isolated from biopsy tissue samples of African children affected by a peculiar B cell–derived tumor, endemic Burkitt's lymphoma. 1 EBV integration can be detected in virtually all endemic Burkitt's lymphoma cases. In addition, a series of molecular evidence supported the hypothesis of a pivotal role of the virus in endemic Burkitt's lymphoma pathogenesis.2, 3, and 4 Subsequently, an association with EBV was also described for other B-cell neoplasms; specifically, EBV is currently recognized as a causative agent of posttransplant lymphomas and is linked to a subset of classical Hodgkin's lymphomas. In addition, EBV was associated with a series of rare T-cell malignancies, usually arising in China, Taiwan, Japan, and Central/South America, but rare in Western countries. 5 Finally, EBV infection was also related to nasopharyngeal carcinoma, a tumor frequently encountered among the Cantonese Chinese, Alaskan Inuits, and Mediterranean Africans, and to rare smooth muscle sarcomas occurring in children with AIDS. 1
This article includes a discussion of the most updated hypothesis on the molecular events leading to EBV-driven T-cell transformation and review pathobiological features of EBV-related T/natural killer (NK) cell malignancies in light of the recent World Health Organization (WHO) Classification of Tumors of the Hematopoietic and Lymphoid Tissues, based on the authors' experience as well as the most updated literature.
EBV-driven T-cell transformation
Although the exact mechanism of action through which EBV causes cancer is unknown, its ability to infect B cells and determine proliferation, clonal expansion, and eventually immortalization is well recognized. 6
EBV encodes multiple viral proteins that have profound effects on cellular expression. The EBV oncogene, LMP1, is essential for EBV transformation of lymphocytes and is the only EBV gene product that has transforming ability in rodent fibroblasts. 1 The encoded viral protein latent membrane protein 1 (LMP1) interacts with signal transducer proteins belonging to the tumor necrosis factor (TNF) family of receptors (TRAFs). 7 LMP1 apparently acts as a constitutively activated TRAF molecule, inducing nuclear factor κB (NF-κB) activation.1 and 8 Specifically, LMP1 induces expression of many important cellular genes that have profound effects on cellular growth, including the epidermal growth factor receptor, antiapoptotic genes such as BCL2 and A20, B-cell activation markers including major histocompatibility complex class I, adhesion molecules such as intercellular adhesion molecule 1, and proteins involved in invasion and metastasis such as matrix metalloproteinase 9 and vascular epidermal growth factor. 1 LMP2 is also an integral membrane protein that has been shown to interfere with signal transduction from the activated immunoglobulin receptor, 9 inhibiting B-cell receptor signaling and preventing activation of the viral replicative cycle. Finally, β-catenin activation may also contribute to the oncogenic process in EBV-infected B lymphocytes, as possibly happens in epithelial cancers. 1
With regard to T/NK tumors, based on the strong racial association, it has been postulated that a genetic-based impaired immune response against EBV may contribute to disease development. 5 In addition, a 30-bp deletion within the LMP1 gene locus has been recognized in most cases, suggesting a possible role for such an abnormality. Sometimes the tumors develop soon after primary EBV infection or in association with chronic active EBV infection (CAEBV). The term CAEBV was coined to describe an infectious mononucleosis-like syndrome persisting for at least 6 months and associated with high titers of antibodies to EBV-capsid antigen (VCA-IgG) and early antigen (EA-IgG) without association with malignancy, autoimmune diseases, or immunodeficiency.10 and 11 A more severe form of CAEBV characterized by high fever, hepatosplenomegaly, extensive lymphadenopathy, and pancytopenia has been described in Japan.12, 13, and 14 These patients have higher viral copy numbers in peripheral blood (PB), and instead of B cells, T cells or NK cells are EBV infected. These cases frequently develop clonal selection of T-cell populations and progression to overt malignant T-cell malignancy. Importantly, however, it should be noted that CAEBV with monoclonal EBV+ T-cell proliferation is now considered part of the spectrum of systemic EBV+ T-cell lymphoproliferative disorders (LPD) of childhood, 15 and it should not be referred as to CAEBV.
In this setting, it appears again that NF-κB activation mediated by EBV-encoded protein may represent a major contribution to the induction of neoplastic transformation. In particular, compared with control T cells that were sensitive to TNF-α, EBV+ T cells expressing LMP1 appeared resistant to TNF-α-induced apoptosis. 16 In particular, the LMP1 signal could not only upregulate TNF-α secretion in T cells through the TRAF/NF-κB pathways, but also dramatically suppress the expression of TNF receptor (TNFR)-1, thereby blocking the TNF-α-induced apoptotic cascade 16 ( Figure 1 ). Additionally, the adapter protein TRADD was found to be recruited to interact with LMP1 and dissociated from TNFR-1, thus reversing the TNF-α-induced apoptosis in LMP1+ T lymphocytes. Furthermore, TNFR-1 can also be transcriptionally inhibited by the EBV immediate-early protein BZLF-1. Thus, EBV seems to be able to use different strategies to regulate the expression of TNFR-1 in both lytic and latent programs to escape from TNF-α-induced cytotoxicity. 16 Overall, these data suggest that suppression of TNFR-1 might be a strategy for EBV-infected or LMP1 expressed T cells to escape from cytokine injuries and survive or proliferate via the activation of the NF-κB pathway.
In addition, EBV-infected T cells tend to survive and proliferate by upregulating the T-cell-activating receptor CD40 and major histocompatibility complex class II, while downregulating the apoptotic receptor FAS. 16
Immunohistochemical studies on tissues obtained from EBV-associated nasal NK/T-cell lymphoma (NKTCL) and CD8+ peripheral T-cell lymphoma (PTCL) have revealed constitutive activation of NF-κB in neoplastic cells with decreased expression of TRAF-1. 16 Intriguingly, in vivo, the activation of the NF-κB pathway may potentially account not only for the proliferative advantage of EBV+ cells, but also for the drug resistance and hypercytokinemia in patients with aggressive EBV-associated T- or NKTCLs. Therefore, therapeutic targeting of the NF-κB signal may represent a potential alternative in the treatment of EBV-associated T-cell lymphoma with NF-κB activation. 16
Aggressive NK-cell leukemia
Aggressive NK-cell leukemia (ANKL, also known as aggressive NK-cell leukemia/lymphoma) is a systemic neoplastic proliferation of NK cells almost always associated with EBV infection and aggressive clinical course. 17
ANKL is a rare leukemia that is currently thought to derive from circulating NK cells and is much more frequent among Asians than other ethnic populations. 18 Patients are most commonly young to middle-age adults, with a median age of 42 years.19 and 20 There is no clear sex predilection or a slight male predominance.18, 19, 20, 21, 22, 23, 24, 25, 26, and 27 The etiology of ANKL is poorly known, but the strong association with EBV infection definitely suggests a pathogenetic role of the virus. Occasionally, patients have been described as having hypersensitivity to mosquito bites or CAEBV,28 and 29 leading to some overlap with EBV+ T-cell lymphoproliferative disorders of childhood (see below).
Most commonly the disease affects the PB, bone marrow (BM), liver, and spleen, but virtually any organ can be involved. However, because the number of neoplastic cells in the PB and BM can be limited, the disease has been also called ANKL. Indeed, there can be overlap with extranodal NK/T-cell lymphoma (ENKTCL) demonstrating multiorgan involvement (and eventually BM); however, it is unclear whether ANKL really represents the leukemic counterpart of ENKTCL. 26 A few cases have been described as possible evolution from ENKTCL or chronic lymphoproliferative disorders of NK cells;30, 31, 32, and 33 however, some genetic data exist documenting molecular differences between the two entities (see below). On the contrary, some features are distinctive of ANKL, including the significantly younger median age, the high frequency of hepatosplenic and BM involvement, the low frequency of skin lesions, the typical diffuse spread with uniformly fatal outcome, and the frequent expression of CD16.14 and 34
On clinical grounds, patients usually present with fever, constitutional symptoms, and a variable amount of circulating leukemic cells in PB. Pancytopenia, secondary to BM leukemic infiltration and serum lactate dehydrogenase level elevation, is usually recorded. Similar to what is observed in other T-cell malignancies, the disease course can be complicated by coagulopathy, hemophagocytic syndrome, or multiorgan failure.14, 19, 21, 22, 24, 35, and 36
The morphologic features of the tumor are variable; in particular, the leukemic cells can be almost indistinguishable from normal large granular lymphocytes or, rather, present with atypical nuclei (large and irregular, with open chromatin or distinct nucleoli). The cytoplasm is usually abundant, pale, or lightly basophilic, containing fine or bizarre azurophilic granules. The BM infiltration can be massive, focal, or interstitial; reactive histiocytes can be observed, sometimes with hemophagocytosis. Tissue infiltration is usually diffuse and destructive. The cellular population is more often monotonous, with round or irregular nuclei, condensed chromatin, and small nucleoli. Sometimes, however, a remarkable nuclear pleomorphism can be observed, as well as the presence of apoptotic bodies. Necrosis is common, with or without angioinvasion.
The immunophenotype is identical to that of ENKTCL, with ANKL cells being CD2+, sCD3−, CD3ε+, and CD56+ and positive for cytotoxic molecules and differing only for CD16 positivity in most cases (75%). 14 CD11b may be expressed, whereas CD57 is usually negative.23 and 26 Notably, the neoplastic cells express Fas ligand, which can be found in the serum of affected patients.37, 38, and 39
The genetic features of ANKL, as in general of most PTCLs, are not precisely known. Importantly, the T-cell receptor (TCR) genes are in germline configuration and thus cannot be used for clonality testing. Upon cytogenetic analysis, no specific tumor-associated lesions have been identified; nevertheless, some recurrent clonal cytogenetic abnormalities have been described, including del(6)(q21q25) and 11q deletion. 27 Remarkably, significant genetic differences have been recorded distinguishing ANKL and ENKTCL by comparative genomic hybridization. Specifically, 7p−, 17p−, and 1q+ were more frequent, whereas 6q− was less common in ANKL. 40 EBV integration, which occurs in a clonal episomal form, can be proved in approximately 90% of patients.24, 41, and 42
The clinical course of ANKL patients is almost invariably fulminant and the prognosis is consistently unfavorable. In most instances multiorgan failure, coagulopathy, and hemophagocytic syndrome definitely worsen the clinical scenario. Response to chemotherapy is usually poor, and patients achieving an initial remission usually relapse independent of the adopted approach. 14 The median survival is less than 2 months.14, 19, 26, and 27 A deeper understanding of the pathobiology of the disease is definitely warranted to identify possible Achilles' heels and design innovative therapeutic approaches.
EBV+ T-cell lymphoproliferative disorders of childhood
The WHO classification currently includes two major types of EBV-associated T-cell lymphoproliferative disorders (LPD), which were originally described in the pediatric setting. 15 Both occur with higher frequency in Asians and in Native Americans from Central and South America. Hydroa vacciniforme-like lymphoma is a cutaneous malignancy with an indolent clinical course, but it usually progresses over time. 15 Conversely, systemic EBV+ T-cell LPD of childhood has a fulminant clinical course; it may be associated with CAEBV and can be anticipated by a prodromic phase of polyclonal or oligoclonal expansion of EBV-infected T cells. 15
Systemic EBV+ T-cell LPD of childhood
The systemic EBV+ T-cell LPD of childhood is a severe disease occurring in children and young adults, characterized by a clonal proliferation of EBV-infected T cells.5 and 15 It is currently regarded as derived from the malignant transformation of activated T lymphocytes with either CD8+ cytotoxic (more commonly) or CD4+ phenotype. This process can develop following primary acute EBV infection or in the setting of CAEBV. It is characterized by a rapid, fatal progression, with multiorgan failure, coagulopathy, and death, usually from days to weeks, often before a diagnosis is reached. As mentioned above, this disease presents with some overlapping features with ANKL.
In the past systemic EBV+ T-cell LPD of childhood has also been regarded as fulminant EBV+ T-cell LPD of childhood, sporadic fatal infectious mononucleosis, fulminant hemophagocytic syndrome in children in Taiwan; 43 fatal EBV-associated hemophagocytic syndrome in Japan; 44 and severe CAEBV.12, 14, and 45 However, based on clinical, pathologic, and molecular data, all such terms are now included under the definition of systemic EBV+ T-cell LPD of childhood. 15
The incidence of systemic EBV+ T-cell LPD of childhood is definitely higher in Asia, especially in Japan and Taiwan.12, 14, 15, 43, and 44 It has been also reported in Mexican populations, whereas it appears to be rare in Western countries.5 and 15 Different from what is suggested by its denomination, the disease is not exclusively seen in the pediatric setting. Indeed, it occurs most often in children, but around half of the patients are young adults, without sex predilection.
The precise etiology of the disease is currently unknown; however, its association with primary EBV infection and the racial predisposition strongly suggest a genetic defect in the host immune response to EBV.12, 14, 15, 43, and 44
Conversely, although not completely understood, the molecular pathogenesis has been referred, as for other EBV+ T-cell malignancies, to the activation of the NF-κB pathway, mediated by some viral components (see below).
On clinical grounds, the disease typically has an acute onset characterized by fever and general symptoms suggestive of an acute infection. Because systemic EBV+ T-cell LPD of childhood is a systemic disease, all organ and tissues can be affected. Nevertheless, the most commonly involved sites are the liver and spleen, followed by the lymph nodes, BM, skin, and lung.5, 12, 14, 15, 43, and 44 Within a short period (weeks to months), patients usually develop hepatosplenomegaly and liver failure. Laboratory findings include pancytopenia (caused by BM infiltration or often the onset of a hemophagocytic syndrome), altered liver function tests, and possibly abnormal EBV serology with low or absent anti-VCA IgM antibodies. Further, the disease is frequently complicated by sepsis, coagulopathy (including disseminated intravascular coagulopathy), and multiorgan failure.5 and 15
At morphology, the infiltrating T cells are typically small and lack significant cytologic features of atypia.5 and 15 However, cases with pleomorphic larger cells, irregular nuclei, and frequent mitoses have been described5 and 14 ( Figure 2 ). The liver and spleen show mild to marked sinusoidal infiltration, sometimes with prominent signs of hemophagocytosis. In particular, the splenic white pulp is depleted, whereas on liver sections marked portal and sinusoidal infiltration, cholestasis, steatosis, and necrosis can be observed. The lymph nodes usually exhibit preserved architecture, but a variable degree of sinus histiocytosis with erythrophagocytosis is usually present. The BM biopsies usually exhibit histiocytic hyperplasia with prominent erythrophagocytosis. 15
At immunophenotypic analysis, neoplastic cells are more often CD2+ CD3+ CD56− and TIA+. Most cases secondary to acute primary EBV infection are CD8+15, 43, and 46 ( Figure 2 ), whereas cases arising in the setting of severe CAEBV are CD4+.15, 47, and 48 Rare cases present with concomitant CD4+ and CD8+ positive staining, 15 a feature sometimes encountered in PTCLs. 49 By definition, in situ hybridization (ISH) for EBV-encoded RNA is positive ( Figure 2 ).
Molecular analyses usually show rearranged TCR genes. Notably, EBV is found in a clonal episomal form in all instances,12, 14, 44, and 47 frequently presenting a 30-bp deletion within the LMP1 gene.14, 15, and 46 Conversely, so far no consistent chromosomal aberrations have been identified.12 and 50 The prognosis is dismal, with most cases having a fulminant clinical course resulting in death within a short period (days to weeks). More rarely, the disease assumes a subacute course of several months to 1 year. 15
Hydroa vacciniforme-like lymphoma
Hydroa vacciniforme-like lymphoma is an EBV+ cutaneous T-cell lymphoma occurring in children and young adults, which is thought to represent the malignant form of skin-homing cytotoxic T cells or NK cells. 15
Like other EBV+ T-cell lymphomas, this disease is more frequently recorded in Asian populations and in Native Americans from Central and South America. 15 A genetic predisposition has been postulated, related to a defective cytotoxic immune response to EBV.15, 51, and 52
The disease basically involves the skin, primarily affecting sun-exposed areas, in particular the face.15, 53, and 54 On clinical grounds, it is characterized by a papulovesicular eruption that usually evolves to ulceration and scarring. In some cases, systemic symptoms including fever, wasting, lymphadenopathy, and hepatosplenomegaly may be present, particularly in later disease stages.51 and 55 Intriguingly, patients exhibit hypersensitivity to sunlight and insect bites, often mosquito bites, which precipitate clinical symptoms.15 and 34
At morphology, the neoplastic cells are generally small to medium size without significant atypia. The neoplastic infiltrates usually extend from the epidermis to the subcutis, showing necrosis, angiocentricity, and angioinvasion. The overlying epidermis is frequently ulcerated.15 and 51
At immunophenotype, the cells typically have a cytotoxic T-cell or, less often, NK-cell profile, with CD56 expression. The genetic features are variable, according to the cellular derivation. Specifically, most cases have clonal rearrangements of the TCR genes. Conversely, cases of NK derivation present with TCR genes in germline configuration.55 and 56 Type A monoclonal EBV (studied by terminal repeat analysis) is found in all instances. At ISH, EBV-encoded RNA is found to be expressed in all atypical cells; conversely, LMP1 is generally negative.
The clinical course is variable but never absolutely benign. In particular, patients may have an indolent course with recurrent skin lesions for some time, up to 10-15 years, before progression to systemic involvement. With systemic spread, the clinical course is much more aggressive.15 and 57
Extranodal NK/T-cell lymphoma, nasal type
ENKTCL, nasal type (formerly known as angiocentric T-cell lymphoma or malignant midline reticulosis or lethal midline granuloma), is a predominantly extranodal lymphoma characterized by vascular damage and destruction, prominent necrosis, cytotoxic phenotype, and association with EBV. 58 The normal counterpart is postulated to be activated NK cells; however, less commonly, an analogue tumor can derive from cytotoxic T lymphocytes. Accordingly, the tumor is designated as NK/T (instead of NK).
ENKTCL is more prevalent in Asians and in the Native American population of Mexico, Central America, and South America.26, 59, 60, and 61 It occurs most often in adults and is more common in males than females.
The etiology of this disease is largely unknown. However, the strong association with EBV, irrespective of the ethnic origin of the patients, suggests a probable pathogenic role of the virus.24, 62, 63, 64, 65, 66, and 67 Similarly to what is observed in the above-described entities, EBV (always of subtype A) is present in a clonal episomal form,61, 62, 63, 64, 65, 67, 68, 69, and 70 with type II latency pattern (EBNA1+, EBNA2−, LMP1+), and commonly exhibits a 30-bp deletion in the LMP1 gene.64, 71, 72, 73, and 74
ENKTCL can occur in both immunocompetent and immunodepressed subjects, including the posttransplant setting.75 and 76 The disease typically arises with extranodal presentation. The upper aerodigestive tract (nasal cavity, nasopharynx, paranasal sinuses, palate) is most commonly involved, with the nasal cavity being the prototypic site of involvement. 58 The extranasal involvement more often includes the skin, soft tissue, gastrointestinal tract, and testis. Some cases may be accompanied by secondary lymph node involvement.24, 25, 26, 77, 78, and 79 The occurrence of primary lymph node disease in the absence of extranodal involvement is, conversely, rare.80, 81, and 82
The clinical picture is usually dependent on local invasion. In particular, patients with nasal involvement tend to present with symptoms of nasal obstruction, or epistaxis, or with extensive midfacial destructive lesions. 58 The lymphoma can then infiltrate adjacent tissues such as the nasopharynx, paranasal sinuses, orbit, oral cavity, palate, and oropharynx. Indeed, the disease is more often localized to these areas, and BM involvement is uncommon. 83 However, neoplastic cells can rapidly disseminate to other sites, including skin, gastrointestinal tract, testis, or cervical lymph nodes during the clinical course. In some instances, in addition, a hemophagocytic syndrome can degenerate the clinical scenario.25 and 84
When the tumor develops outside the upper aerodigestive tract (often referred to as extranasal NKTCL), the clinical presentation again relies upon the major site of involvement. Skin lesions are commonly nodular, often with ulceration as more often seen in the mucosal lesions. Intestinal lesions often manifest as perforation. Other involved sites often present as mass lesions. 58 The patients usually present with advanced-stage disease, with involvement of multiple extranodal sites and possible systemic symptoms.24, 77, and 85 Lymph nodes can be involved as part of disseminated disease. BM and PB involvement can also occur, and such cases may overlap with ANKL (see above).
The histologic features of ENKTCL are similar irrespective of the site of involvement 58 ( Figure 3 ). The neoplastic infiltrate is diffusely invasive. An angiocentric and angiodestructive growth pattern is frequently present, and fibrinoid changes can be seen in the blood vessels even in the absence of angioinvasion. 58 Coagulative necrosis and admixed apoptotic bodies are common. The latter phenomena have been previously attributed to vascular occlusion by tumor cells, but recent studies demonstrated the possible involvement of other factors, such as chemokines and cytokines.58 and 86
The cytologic features can be largely variable. Cells may be small, medium size, large, or anaplastic. In most cases, however, the tumor is formed by medium-size cells or a mixture of small and large cells ( Figure 3 ). Mitotic figures are easily found, even for small cell-predominant lesions. A moderate amount of pale to clear cytoplasm is typical; azurophilic granules are commonly detected in cytologic preparations stained by Giemsa. Nuclei are often irregularly folded and sometimes elongated. The chromatin is granular in small to medium-size elements and tends to be vesicular in larger cells. Nucleoli are generally inconspicuous or small. In some instances, a conspicuous admixture of inflammatory cells (small lymphocytes, plasma cells, histiocytes, and eosinophils) is present, with the process thus mimicking an inflammatory process.26 and 30 The mucosal lesion can sometimes be accompanied by florid pseudoepitheliomatous hyperplasia of the overlying epithelium. 58
At immunophenotyping, the neoplastic cells are typically CD2+, CD56+, sCD3−, and cCD3 ε+.26, 87, 88, 89, and 90 The cytotoxic molecules granzyme B, TIA1, and perforin are positive. Other T- and NK-cell-associated antigens are usually negative, including CD4, CD5, CD8, TCRδ, βF1, CD16, and CD57. Conversely, CD43, CD45RO, HLA-DR, CD25, Fas (CD95), and Fas ligand are commonly expressed58, 91, and 92 ( Figure 3 ). Occasional cases are positive for CD7 or CD30. 73 Cases demonstrated to be CD3ε+ and CD56− are still classified as ENKTCL only if both cytotoxic molecules and EBV are positive.58 and 93 By contrast, nasal or other extranodal lymphomas that are CD3+, CD56−, but negative for EBV and cytotoxic molecules should be diagnosed as PTCL, not otherwise specified (PTCL/NOS).
By definition, EBV integration can be demonstrated in all cases by ISH for EBV-encoded RNA. Conversely, immunostaining for EBV-associated antigens such as LMP1 is not consistent.
At molecular analysis, TCR genes are in germline configuration in most cases. Conversely, in a small proportion of cases, the TCR genes exhibit clonal rearrangement, corresponding to the cases of cytotoxic T-lymphocyte derivation.58, 74, 93, and 94 Different from what is reported for the previously discussed entities, a variety of cytogenetic aberrations have been associated with ENKTCL, although no specific chromosomal translocations have been identified so far. The most common cytogenetic abnormality is del(6)(q21q25) or i(6)(p10), but it is currently unclear whether this is a primary or progression-associated event.95, 96, 97, and 98 Aberrant methylation of promoter CpG regions of multiple genes is common, in particular involving TP73. 99 Comparative genomic hybridization studies identified some recurrent genomic imbalances including gain of 2q and loss of 1p36.23-p36.33, 6q16.1-q27, 4q12, 5q34-q35.3, 7q21.3-q22.1, 11q22.3-q23.3, and 15q11.2-q14. 40 A proportion of cases exhibit partial deletion of the FAS gene or mutation in TP53, CTNNB1, KRAS, or KIT genes, but the significance is still unclear.100, 101, and 102
Recently, ENKTCL was the object of a combined gene expression profiling (GEP) and array-based comparative genomic hybridization analysis. 103 Compared with PTCL/NOS ENKTCL had higher transcript levels for NK-cell markers and cytotoxic molecules, especially granzyme H, a novel sensitive biomarker of NKTCL. 103 Compared with normal NK cells, tumors were closer to activated than resting cells and overexpressed several genes related to vascular biology, EBV-induced genes, and PDGFRA. Notably, PDGFRA expression and activation (ie, phosphorylation) were confirmed at the protein level, and in vitro the MEC04 NKTCL cell line was sensitive to imatinib. 103 Remarkably, an analogue observation was also done in the field of PTCL/NOS and angioimmunoblastic lymphoma,104, 105, and 106 highlighting the importance of PDGFRA deregulation in the pathogenesis of different T/NK-derived malignancies. In addition, deregulation of the AKT, JAK/STAT, and NF-κB pathways was identified by GEP and further corroborated by immunohistochemistry and comparative genomic hybridization. In particular, nuclear expression of phosphorylated AKT, STAT3, and RELA was documented in NKTCL, and several genes belonging to these pathways actually mapped in regions of recurrent copy number aberrations [AKT3 (1q44), IL6R (1q21.3), CCL2 (17q12), and TNFRSF21 (6p12.3)]. 103 Interestingly, other NKTCL features uncovered by GEP analysis suggested an activation of angiogenic pathways, including overexpression of VEGFA and its receptor KDR by the tumor cells and overexpression of MET-HGF. Finally, this analysis also evidenced deregulation of the tumor suppressor HACE1 in the frequently deleted 6q21 region. Overall, GEP provided important insights into NKTCL pathogenesis, also offering a rational basis for novel targeted therapeutic approaches. 103
The prognosis of ENKTCL is poor, possibly the worst among the PTCL categories.107 and 108 Specifically, the survival rate is 30%–40%, although some differences exist between nasal and nonnasal disease because the latter is more aggressive.26, 107, and 109 Recently, the inclusion of radiotherapy in treatment protocols improved the outcome of nasal NK/T-cell lymphoma in stage I or II.73, 107, 109, 110, and 111 Among nasal forms, adverse prognostic factors are unfavorable International Prognostic Index (IPI), advanced stage disease (stage III or IV), high circulating EBV DNA levels, and detection of EBV in BM cells by ISH.93, 107, 109, 111, 112, 113, 114, and 115 Some studies suggest that a high proportion of large/transformed cells in the tumor population have a negative impact on survival, but the significance of cytologic features as a prognostic indicator is still uncertain.25, 107, 109, and 110 The primary extranasal cases are highly aggressive with poor response to therapy, even in patients with localized disease.107 and 109
Importantly, a new prognostic index proposed by a Korean group, specifically developed for NK/T cell tumors and based on 4 parameters (“B” symptoms, lactate dehydrogenase levels, stage, and regional lymph node involvement), demonstrated better prognostic stratification of NKTCLs compared with International Prognostic Index (IPI).116 and 108
In addition, another study recently demonstrated 4 significant prognostic factors in NKTCLs (nonnasal type, stage, performance status, and numbers of extranodal involvement).117 and 108 Using these 4 variables, an NK prognostic index was successfully constructed, with 4-year overall survival of patients with 0, 1, 2, and 3 or 4 adverse factors being 55%, 33%, 15%, and 6%, respectively. 117
In conclusion, though EBV has been historically related to the pathogenesis of specific B-cell derived malignancies, there are emerging evidences supporting its role in the transformation of T-lymphocytes and NK-cells as well. In particular, in the last edition of the WHO classification, different entities were by definition associated to the viral infection. Noteworthy, these disease are indeed variable as far as both biology and clinic are concerned. Their prognosis is generally poor; however, a systematic characterization by high throughput genomics may lead in the near future to the identification of novel targets for innovative therapies as in the case of PDGFRA+ ENKTCLs, which may possibly benefit of tyrosine kinase inhibitors.
We are grateful to Dr Marco Bettuzzi for figure editing. This work was supported by Centro Interdipartimentale per la Ricerca sul Cancro “G. Prodi,” BolognAIL, AIRC (IG4987, IG10007; 5xMille), RFO (Prof Pileri, Dr Piccaluga), Fondazione Cassa di Risparmio in Bologna, Fondazione della Banca del Monte, e Ravenna, and Progetto Strategico di Ateneo 2006 (Prof Pileri and Dr Piccaluga). The authors have no conflicting financial interests to declare.
- 1 J.S. Pagano, M. Blaser, M.A. Buendia, et al. Infectious agents and cancer: criteria for a causal relation. Semin Cancer Biol. 2004;14:453-471 Crossref.
- 2 G. De Falco, G. Antonicelli, A. Onnis, et al. Role of EBV in microRNA dysregulation in Burkitt lymphoma. Semin Cancer Biol. 2009;19:401-406 Crossref.
- 3 E. Leucci, A. Onnis, M. Cocco, et al. B-cell differentiation in EBV-positive Burkitt lymphoma is impaired at posttranscriptional level by miRNA-altered expression. Int J Cancer. 2011;126:1316-1326
- 4 P.P. Piccaluga, G. De Falco, M. Kustagi, et al. Gene expression analysis uncovers similarity and differences among Burkitt lymphoma subtypes. Blood. 18 January 2011; Epub ahead of print
- 5 V. Tabanelli, C. Agostinelli, E. Sabattini, et al. Systemic EBV+ T-cell lymphoproliferative disease of childhood in Western countries: A case report and review of literature. J Med Case Rep. 2011; in press
- 6 J.H. Pope, W. Scott, D.J. Moss. Human lymphoid cell transformation by Epstein–Barr virus. Nat New Biol. 1973;246:140-141 Crossref.
- 7 G. Mosialos, M. Birkenbach, R. Yalamanchili, et al. The Epstein–Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell. 1995;80:389-399 Crossref.
- 8 W.E. Miller, J.L. Cheshire, N. Raab-Traub. Interaction of tumor necrosis factor receptor-associated factor signaling proteins with the latent membrane protein 1 PXQXT motif is essential for induction of epidermal growth factor receptor expression. Mol Cell Biol. 1998;18:2835-2844
- 9 C.L. Miller, J.H. Lee, E. Kieff, et al. An integral membrane protein (LMP2) blocks reactivation of Epstein–Barr virus from latency following surface immunoglobulin crosslinking. Proc Natl Acad Sci U S A. 1994;91:772-776 Crossref.
- 10 L. Quintanilla-Martinez, H. Kimura, E.S. Jaffe. E.B.V-positive T-cell lymphoproliferative disorders of childhood. S. Swerdlow (Ed.) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (IARC, Lyon, 2008) 278-280
- 11 S.E. Straus. The chronic mononucleosis syndrome. J Infect Dis. 1988;157:405-412 Crossref.
- 12 H. Kimura, Y. Hoshino, H. Kanegane, et al. Clinical and virologic characteristics of chronic active Epstein–Barr virus infection. Blood. 2001;98:280-286 Crossref.
- 13 H. Kimura, T. Morishima, H. Kanegane, et al. Prognostic factors for chronic active Epstein–Barr virus infection. J Infect Dis. 2003;187:527-533 Crossref.
- 14 K. Suzuki, K. Ohshima, K. Karube, et al. Clinicopathological states of Epstein–Barr virus-associated T/NK-cell lymphoproliferative disorders (severe chronic active EBV infection) of children and young adults. Int J Oncol. 2004;24:1165-1174
- 15 L. Quintanilla-Martinez, S. Kumar, F. Fend, et al. Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome. Blood. 2000;96:443-451
- 16 H.C. Chuang, J.D. Lay, W.C. Hsieh, et al. Pathogenesis and mechanism of disease progression from hemophagocytic lymphohistiocytosis to Epstein–Barr virus-associated T-cell lymphoma: nuclear factor-kappa B pathway as a potential therapeutic target. Cancer Sci. 2007;98:1281-1287 Crossref.
- 17 J.K.C. Chan, E.S. Jaffe, E. Ralfkiaer. Aggressive NK-cell leukaemia. S. Swerdlow (Ed.) et al. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (ed 4) (IARC, Lyon, 2008) 276-277
- 18 A. Ruskova, R. Thula, G. Chan. Aggressive natural killer-cell leukemia: report of five cases and review of the literature. Leuk Lymphoma. 2004;45:2427-2438
- 19 S.Y. Song, W.S. Kim, Y.H. Ko, et al. Aggressive natural killer cell leukemia: clinical features and treatment outcome. Haematologica. 2002;87:1343-1345
- 20 R. Suzuki, J. Suzumiya, S. Nakamura, et al. Aggressive natural killer-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells. Leukemia. 2004;18:763-770 Crossref.
- 21 N. Imamura, Y. Kusunoki, K. Kawa-Ha, et al. Aggressive natural killer cell leukaemia/lymphoma: report of four cases and review of the literature: Possible existence of a new clinical entity originating from the third lineage of lymphoid cells. Br J Hæmatol. 1990;75:49-59
- 22 Y.L. Kwong, K.F. Wong, L.C. Chan, et al. Large granular lymphocyte leukemia: A study of nine cases in a Chinese population. Am J Clin Pathol. 1995;103:76-81
- 23 K. Oshimi. Lymphoproliferative disorders of natural killer cells. Int J Hematol. 1996;63:279-290 Crossref.
- 24 J.K. Chan, V.C. Sin, K.F. Wong, et al. Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood. 1997;89:4501-4513
- 25 Y.L. Kwong, A.C. Chan, R. Liang, et al. CD56+ NK lymphomas: clinicopathological features and prognosis. Br J Haematol. 1997;97:821-829
- 26 J.K. Chan. Natural killer cell neoplasms. Anat Pathol. 1998;3:77-145
- 27 J. Ryder, X. Wang, L. Bao, et al. Aggressive natural killer cell leukemia: report of a Chinese series and review of the literature. Int J Hematol. 2007;85:18-25 Crossref.
- 28 S. Ishihara, S. Okada, H. Wakiguchi, et al. Clonal lymphoproliferation following chronic active Epstein–Barr virus infection and hypersensitivity to mosquito bites. Am J Hematol. 1997;54:276-281 Crossref.
- 29 S. Ishihara, K. Ohshima, Y. Tokura, et al. Hypersensitivity to mosquito bites conceals clonal lymphoproliferation of Epstein-Barr viral DNA-positive natural killer cells. Jpn J Cancer Res. 1997;88:82-87 Crossref.
- 30 R.P. Hasserjian, N.L. Harris. NK-cell lymphomas and leukemias: a spectrum of tumors with variable manifestations and immunophenotype. Am J Clin Pathol. 2007;127:860-868 Crossref.
- 31 Y. Ohno, R. Amakawa, S. Fukuhara, et al. Acute transformation of chronic large granular lymphocyte leukemia associated with additional chromosome abnormality. Cancer. 1989;64:63-67 Crossref.
- 32 K. Oshimi, O. Yamada, T. Kaneko, et al. Laboratory findings and clinical courses of 33 patients with granular lymphocyte-proliferative disorders. Leukemia. 1993;7:782-788
- 33 J. Soler, R. Bordes, F. Ortuno, et al. Aggressive natural killer cell leukaemia/lymphoma in two patients with lethal midline granuloma. Br J Hæmatol. 1994;86:659-662 Crossref.
- 34 V.E. Nava, E.S. Jaffe. The pathology of NK-cell lymphomas and leukemias. Adv Anat Pathol. 2005;12:27-34 Crossref.
- 35 T. Okuda, S. Sakamoto, T. Deguchi, et al. Hemophagocytic syndrome associated with aggressive natural killer cell leukemia. Am J Hematol. 1991;38:321-323 Crossref.
- 36 N. Mori, Y. Yamashita, T. Tsuzuki, et al. Lymphomatous features of aggressive NK cell leukaemia/lymphoma with massive necrosis, haemophagocytosis and EB virus infection. Histopathology. 2000;37:363-371 Crossref.
- 37 K. Kato, K. Ohshima, S. Ishihara, et al. Elevated serum soluble Fas ligand in natural killer cell proliferative disorders. Br J Hæmatol. 1998;103:1164-1166 Crossref.
- 38 H. Makishima, T. Ito, K. Momose, et al. Chemokine system and tissue infiltration in aggressive NK-cell leukemia. Leuk Res. 2007;31:1237-1245 Crossref.
- 39 M. Tanaka, T. Suda, K. Haze, et al. Fas ligand in human serum. Nat Med. 1996;2:317-322 Crossref.
- 40 Y. Nakashima, H. Tagawa, R. Suzuki, et al. Genome-wide array-based comparative genomic hybridization of natural killer cell lymphoma/leukemia: different genomic alteration patterns of aggressive NK-cell leukemia and extranodal Nk/T-cell lymphoma, nasal type. Genes Chromosomes Cancer. 2005;44:247-255 Crossref.
- 41 K. Kawa-Ha, S. Ishihara, T. Ninomiya, et al. CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein–Barr viral DNA. J Clin Invest. 1989;84:51-55 Crossref.
- 42 D.N. Hart, B.W. Baker, M.J. Inglis, et al. Epstein–Barr viral DNA in acute large granular lymphocyte (natural killer) leukemic cells. Blood. 1992;79:2116-2123
- 43 I.J. Su, R.L. Chen, D.T. Lin, et al. Epstein–Barr virus (EBV) infects T lymphocytes in childhood EBV-associated hemophagocytic syndrome in Taiwan. Am J Pathol. 1994;144:1219-1225
- 44 H. Kikuta, Y. Sakiyama, S. Matsumoto, et al. Fatal Epstein–Barr virus-associated hemophagocytic syndrome. Blood. 1993;82:3259-3264
- 45 M. Okano, S. Matsumoto, T. Osato, et al. Severe chronic active Epstein–Barr virus infection syndrome. Clin Microbiol Rev. 1991;4:129-135
- 46 Y. Kasahara, A. Yachie, K. Takei, et al. Differential cellular targets of Epstein–Barr virus (EBV) infection between acute EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection. Blood. 2001;98:1882-1888 Crossref.
- 47 J.F. Jones, S. Shurin, C. Abramowsky, et al. T-cell lymphomas containing Epstein–Barr viral DNA in patients with chronic Epstein–Barr virus infections. N Engl J Med. 1988;318:733-741 Crossref.
- 48 H. Kanegane, K. Bhatia, M. Gutierrez, et al. A syndrome of peripheral blood T-cell infection with Epstein–Barr virus (EBV) followed by EBV-positive T-cell lymphoma. Blood. 1998;91:2085-2091
- 49 P. Went, C. Agostinelli, A. Gallamini, et al. Marker expression in peripheral T-cell lymphoma: a proposed clinical–pathologic prognostic score. J Clin Oncol. 2006;24:2472-2479 Crossref.
- 50 J.S. Chen, C.C. Tzeng, C.J. Tsao, et al. Clonal karyotype abnormalities in EBV-associated hemophagocytic syndrome. Haematologica. 1997;82:572-576
- 51 C. Barrionuevo, V.M. Anderson, E. Zevallos-Giampietri, et al. Hydroa-like cutaneous T-cell lymphoma: a clinicopathologic and molecular genetic study of 16 pediatric cases from Peru. Appl Immunohistochem Mol Morphol. 2002;10:7-14 Crossref.
- 52 K.H. Cho, C.W. Kim, D.S. Heo, et al. Epstein–Barr virus-associated peripheral T-cell lymphoma in adults with hydroa vacciniforme-like lesions. Clin Exp Dermatol. 2001;26:242-247 Crossref.
- 53 K. Doeden, H. Molina-Kirsch, E. Perez, et al. Hydroa-like lymphoma with CD56 expression. J Cutan Pathol. 2008;35:488-494 Crossref.
- 54 K. Iwatsuki, Z. Xu, M. Ohtsuka, et al. Cutaneous lymphoproliferative disorders associated with Epstein–Barr virus infection: a clinical overview. J Dermatol Sci. 2000;22:181-195 Crossref.
- 55 H.H. Chen, C.H. Hsiao, H.C. Chiu. Hydroa vacciniforme-like primary cutaneous CD8-positive T-cell lymphoma. Br J Dermatol. 2002;147:587-591 Crossref.
- 56 Y.H. Wu, H.C. Chen, P.F. Hsiao, et al. Hydroa vacciniforme-like Epstein–Barr virus-associated monoclonal T-lymphoproliferative disorder in a child. Int J Dermatol. 2007;46:1081-1086 Crossref.
- 57 Y. Nitta, K. Iwatsuki, H. Kimura, et al. Fatal natural killer cell lymphoma arising in a patient with a crop of Epstein–Barr virus-associated disorders. Eur J Dermatol. 2005;15:503-506
- 58 J.K.C. Chan, L. Quintanilla-Martinez, J.A. Ferry, et al. Extranodal NK/T-cell lymphoma nasal type. S. Swerdlow (Ed.) et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (IARC, Lyon, 2008) 285-288
- 59 The World Health Organization. Classification of malignant lymphomas in Japan: incidence of recently recognized entities: Lymphoma Study Group of Japanese Pathologists. Pathol Int. 2000;50:696-702
- 60 W.Y. Au, S.Y. Ma, C.S. Chim, et al. 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. Ann Oncol. 2005;16:206-214 Crossref.
- 61 L. Quintanilla-Martinez, J.L. Franklin, I. Guerrero, et al. Histological and immunophenotypic profile of nasal NK/T cell lymphomas from Peru: high prevalence of p53 overexpression. Hum Pathol. 1999;30:849-855 Crossref.
- 62 D.A. Arber, L.M. Weiss, P.F. Albujar, et al. Nasal lymphomas in Peru: High incidence of T-cell immunophenotype and Epstein–Barr virus infection. Am J Surg Pathol. 1993;17:392-399 Crossref.
- 63 J.K. Chan, T.T. Yip, W.Y. Tsang, et al. Detection of Epstein–Barr viral RNA in malignant lymphomas of the upper aerodigestive tract. Am J Surg Pathol. 1994;18:938-946 Crossref.
- 64 K.S. Elenitoba-Johnson, A. Zarate-Osorno, A. Meneses, 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;11:754-761
- 65 P. Kanavaros, M.C. Lescs, J. Briere, et al. Nasal T-cell lymphoma: a clinicopathologic entity associated with peculiar phenotype and with Epstein–Barr virus. Blood. 1993;81:2688-2695
- 66 L. Quintanilla-Martinez, F. Fend, L.R. Moguel, 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;23:1233-1240 Crossref.
- 67 J. van Gorp, L. Weiping, K. Jacobse, et al. Epstein–Barr virus in nasal T-cell lymphomas (polymorphic reticulosis/midline malignant reticulosis) in western China. J Pathol. 1994;173:81-87 Crossref.
- 68 M. Hummel, S. Bentink, H. Berger, et al. A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. N Engl J Med. 2006;354:2419-2430 Crossref.
- 69 L.J. Medeiros, S.C. Peiper, L. Elwood, et al. Angiocentric immunoproliferative lesions: a molecular analysis of eight cases. Hum Pathol. 1991;22:1150-1157
- 70 J. Suzumiya, K. Ohshima, M. Takeshita, et al. Nasal lymphomas in Japan: a high prevalence of Epstein–Barr virus type A and deletion within the latent membrane protein gene. Leuk Lymphoma. 1999;35:567-578 Crossref.
- 71 A.K. Chiang, K.Y. Wong, A.C. Liang, et al. Comparative analysis of Epstein–Barr virus gene polymorphisms in nasal T/NK-cell lymphomas and normal nasal tissues: implications on virus strain selection in malignancy. Int J Cancer. 1999;80:356-364 Crossref.
- 72 S. Dirnhofer, A. Angeles-Angeles, C. Ortiz-Hidalgo, et al. High prevalence of a 30-base pair deletion in the Epstein–Barr virus (EBV) latent membrane protein 1 gene and of strain type B EBV in Mexican classical Hodgkin's disease and reactive lymphoid tissue. Hum Pathol. 1999;30:781-787 Crossref.
- 73 T.T. Kuo, L.Y. Shih, N.M. Tsang, et al. NK/T cell lymphoma in Taiwan: a clinicopathologic study of 22 cases, with analysis of histologic subtypes, Epstein–Barr virus LMP-1 gene association, and treatment modalities. Int J Surg Pathol. 2004;12:375-387 Crossref.
- 74 Y.C. Tai, L.H. Kim, S.C. Peh. High frequency of EBV association and 30-bp deletion in the LMP-1 gene in CD56 lymphomas of the upper aerodigestive tract. Pathol Int. 2004;54:158-166 Crossref.
- 75 Y. Hoshida, T. Li, Z. Dong, et al. Lymphoproliferative disorders in renal transplant patients in Japan. Int J Cancer. 2001;91:869-875 Crossref.
- 76 Y.L. Kwong, C.C. Lam, T.M. Chan. Post-transplantation lymphoproliferative disease of natural killer cell lineage: a clinicopathological and molecular analysis. Br J Hæmatol. 2000;110:197-202 Crossref.
- 77 W.F. Kern, C.M. Spier, E.H. Hanneman, et al. Neural cell adhesion molecule-positive peripheral T-cell lymphoma: a rare variant with a propensity for unusual sites of involvement. Blood. 1992;79:2432-2437
- 78 T. Petrella, M.H. Delfau-Larue, D. Caillot, et al. Nasopharyngeal lymphomas: further evidence for a natural killer cell origin. Hum Pathol. 1996;27:827-833 Crossref.
- 79 Y. Tomita, M. Ohsawa, K. Qiu, et al. Epstein–Barr virus in lymphoproliferative diseases in the sino-nasal region: close association with CD56+ immunophenotype and polymorphic-reticulosis morphology. Int J Cancer. 1997;70:9-13 Crossref.
- 80 C.S. Chim, E.S. Ma, F. Loong, et al. Diagnostic cues for natural killer cell lymphoma: primary nodal presentation and the role of in situ hybridisation for Epstein–Barr virus encoded early small RNA in detecting occult bone marrow involvement. J Clin Pathol. 2005;58:443-445 Crossref.
- 81 Y. Kagami, R. Suzuki, H. Taji, et al. Nodal cytotoxic lymphoma spectrum: a clinicopathologic study of 66 patients. Am J Surg Pathol. 1999;23:1184-1200 Crossref.
- 82 H. Saffer, A. Wahed, G.Z. Rassidakis, et al. Clusterin expression in malignant lymphomas: a survey of 266 cases. Mod Pathol. 2002;15:1221-1226 Crossref.
- 83 K.F. Wong, J.K. Chan, M.M. Cheung, et al. Bone marrow involvement by nasal NK cell lymphoma at diagnosis is uncommon. Am J Clin Pathol. 2001;115:266-270
- 84 M.M. Cheung, J.K. Chan, W.H. Lau, et al. Primary non-Hodgkin's lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J Clin Oncol. 1998;16:70-77
- 85 K.F. Wong, J.K. Chan, C.S. Ng, et al. CD56 (NKH1)-positive hematolymphoid malignancies: an aggressive neoplasm featuring frequent cutaneous/mucosal involvement, cytoplasmic azurophilic granules, and angiocentricity. Hum Pathol. 1992;23:798-804 Crossref.
- 86 J. Teruya-Feldstein, E.S. Jaffe, P.R. Burd, et al. The role of Mig, the monokine induced by interferon-gamma, and IP-10, the interferon-gamma-inducible protein-10, in tissue necrosis and vascular damage associated with Epstein–Barr virus-positive lymphoproliferative disease. Blood. 1997;90:4099-4105
- 87 J.K. Chan, W.Y. Tsang, C.S. Ng. Clarification of CD3 immunoreactivity in nasal T/natural killer cell lymphomas: the neoplastic cells are often CD3 epsilon+. Blood. 1996;87:839-841
- 88 E.S. Jaffe. Nasal and nasal-type T/NK cell lymphoma: a unique form of lymphoma associated with the Epstein–Barr virus. Histopathology. 1995;27:581-583 Crossref.
- 89 E.S. Jaffe, J.K. Chan, I.J. Su, et al. Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer cell Lymphomas: Definitions, differential diagnosis, and epidemiology. Am J Surg Pathol. 1996;20:103-111 Crossref.
- 90 W.Y. Tsang, J.K. Chan, C.S. Ng, et al. Utility of a paraffin section-reactive CD56 antibody (123C3) for characterization and diagnosis of lymphomas. Am J Surg Pathol. 1996;20:202-210 Crossref.
- 91 C.S. Ng, S.T. Lo, J.K. Chan, et al. CD56+ putative natural killer cell lymphomas: production of cytolytic effectors and related proteins mediating tumor cell apoptosis?. Hum Pathol. 1997;28:1276-1282 Crossref.
- 92 K. Ohshima, J. Suzumiya, K. Shimazaki, et al. Nasal T/NK cell lymphomas commonly express perforin and Fas ligand: important mediators of tissue damage. Histopathology. 1997;31:444-450
- 93 S.B. Ng, K.W. Lai, S. Murugaya, et al. Nasal-type extranodal natural killer/T-cell lymphomas: a clinicopathologic and genotypic study of 42 cases in Singapore. Mod Pathol. 2004;17:1097-1107 Crossref.
- 94 Y.H. Ko, H.J. Ree, W.S. Kim, et al. Clinicopathologic and genotypic study of extranodal nasal-type natural killer/T-cell lymphoma and natural killer precursor lymphoma among Koreans. Cancer. 2000;89:2106-2116 Crossref.
- 95 L.L. Siu, V. Chan, J.K. Chan, et al. Consistent patterns of allelic loss in natural killer cell lymphoma. Am J Pathol. 2000;157:1803-1809 Crossref.
- 96 L.L. Siu, K.F. Wong, J.K. Chan, et al. Comparative genomic hybridization analysis of natural killer cell lymphoma/leukemia: Recognition of consistent patterns of genetic alterations. Am J Pathol. 1999;155:1419-1425 Crossref.
- 97 H.F. Tien, I.J. Su, J.L. Tang, et al. Clonal chromosomal abnormalities as direct evidence for clonality in nasal T/natural killer cell lymphomas. Br J Hæmatol. 1997;97:621-625
- 98 K.F. Wong, Y.M. Zhang, J.K. Chan. Cytogenetic abnormalities in natural killer cell lymphoma/leukaemia—is there a consistent pattern?. Leuk Lymphoma. 1999;34:241-250
- 99 L.L. Siu, J.K. Chan, K.F. Wong, et al. Specific patterns of gene methylation in natural killer cell lymphomas: p73 is consistently involved. Am J Pathol. 2002;160:59-66
- 100 T. Hongyo, Y. Hoshida, S. Nakatsuka, et al. p53, K-ras, c-kit and beta-catenin gene mutations in sinonasal NK/T-cell lymphoma in Korea and Japan. Oncol Rep. 2005;13:265-271
- 101 L. Quintanilla-Martinez, M. Kremer, G. Keller, et al. p53 mutations in nasal natural killer/T-cell lymphoma from Mexico: association with large cell morphology and advanced disease. Am J Pathol. 2001;159:2095-2105 Crossref.
- 102 L. Shen, A.C. Liang, L. Lu, et al. Frequent deletion of Fas gene sequences encoding death and transmembrane domains in nasal natural killer/T-cell lymphoma. Am J Pathol. 2002;161:2123-2131 Crossref.
- 103 Y. Huang, A. de Reynies, L. de Leval, et al. Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. Blood. 2010;115:1226-1237 Crossref.
- 104 P.P. Piccaluga, C. Agostinelli, P.L. Zinzani, et al. Expression of platelet-derived growth factor receptor alpha in peripheral T-cell lymphoma not otherwise specified. Lancet Oncol. 2005;6:440 Crossref.
- 105 P.P. Piccaluga, C. Agostinelli, A. Califano, et al. Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets. J Clin Invest. 2007;117:823-834 Crossref.
- 106 P.P. Piccaluga, C. Agostinelli, A. Califano, et al. Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation. Cancer Res. 2007;67:10703-10710 Crossref.
- 107 W.Y. Au, D.D. Weisenburger, T. Intragumtornchai, et al. Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project. Blood. 2009;113:3931-3937 Crossref.
- 108 P.P. Piccaluga, C. Agostinelli, A. Gazzola, et al. Prognostic markers in peripheral T-cell lymphoma. Curr Hematol Malignancy Rep. 2010;5:222-228 Crossref.
- 109 J. Chan, L. Quintanilla-Martinez, J. Ferry, et al. Extranodal NK/T-cell lymphoma, nasal-type. S. Swerdlow (Ed.) et al. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (ed 4) (IARC, Lyon, 2008) 285
- 110 C. Barrionuevo, M. Zaharia, M.T. Martinez, et al. Extranodal NK/T-cell lymphoma, nasal type: study of clinicopathologic and prognosis factors in a series of 78 cases from Peru. Appl Immunohistochem Mol Morphol. 2007;15:38-44 Crossref.
- 111 M.M. Cheung, J.K. Chan, W.H. Lau, et al. Early stage nasal NK/T-cell lymphoma: clinical outcome, prognostic factors, and the effect of treatment modality. Int J Radiat Oncol Biol Phys. 2002;54:182-190 Crossref.
- 112 W.Y. Au, A. Pang, C. Choy, et al. Quantification of circulating Epstein–Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients. Blood. 2004;104:243-249 Crossref.
- 113 C.S. Chim, S.Y. Ma, W.Y. Au, et al. Primary nasal natural killer cell lymphoma: long-term treatment outcome and relationship with the International Prognostic Index. Blood. 2004;103:216-221 Crossref.
- 114 W.T. Huang, K.C. Chang, G.C. Huang, et al. Bone marrow that is positive for Epstein–Barr virus encoded RNA-1 by in situ hybridization is related with a poor prognosis in patients with extranodal natural killer/T-cell lymphoma, nasal type. Haematologica. 2005;90:1063-1069
- 115 J. Lee, C. Suh, J. Huh, et al. Effect of positive bone marrow EBV in situ hybridization in staging and survival of localized extranodal natural killer/T-cell lymphoma, nasal-type. Clin Cancer Res. 2007;13:3250-3254 Crossref.
- 116 J. Lee, C. Suh, Y.H. Park, et al. Extranodal natural killer T-cell lymphoma, nasal-type: a prognostic model from a retrospective multicenter study. J Clin Oncol. 2006;24:612-618 Crossref.
- 117 R. Suzuki, J. Suzumiya, M. Yamaguchi, et al. Prognostic factors for mature natural killer (NK) cell neoplasms: aggressive NK cell leukemia and extranodal NK cell lymphoma, nasal type. Ann Oncol. 2010;21:1032-1040 Crossref.
Molecular Pathology Laboratory, Hematopathology Section, Department of Hematology and Oncological Sciences “L. and A. Seràgnoli,” S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Address reprint requests and correspondence: Pier Paolo Piccaluga, MD, PhD, Molecular Pathology Laboratory, Hematopathology Section, Department of Hematology and Oncological Sciences “L. and A. Seràgnoli,” S. Orsola-Malpighi Hospital, University of Bologna, Via Massarenti, 9, 40138 Bologna, Italy
© 2011 Elsevier Inc., All rights reserved.