Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type

INTRODUCTION — The peripheral T cell lymphomas (PTCL) are a heterogeneous group of generally aggressive neoplasms that constitute less than 15 percent of all non-Hodgkin lymphomas (NHL) in adults [1,2]. (See "Classification of hematopoietic neoplasms".)

Among these, in decreasing frequency of occurrence, are:

●Peripheral T cell lymphoma, not otherwise specified (NOS)

●Anaplastic large cell lymphoma, primary systemic type

●Angioimmunoblastic T cell lymphoma

●Extranodal NK/T cell lymphoma, nasal type (ENKL)

●Subcutaneous panniculitis-like T cell lymphoma

●Enteropathy associated T cell lymphoma

●Hepatosplenic T cell lymphoma

Extranodal natural killer/T cell lymphoma, nasal type (ENKL), or nasal NK/T cell lymphoma (formerly called angiocentric lymphoma) most commonly presents in the nasopharynx, but may also involve other extranodal sites. The tumor cells are latently infected with Epstein-Barr virus (EBV) and most cases have a natural killer (NK) cell phenotype.

The clinical presentation, pathologic features, and diagnosis of ENKL will be discussed here. The treatment and prognosis of ENKL are presented separately. (See "Treatment of extranodal NK/T cell lymphoma, nasal type".)

EPIDEMIOLOGY — Nasal-type NK/T cell lymphoma is most common in Asia (eg, China, Japan, Korea, Hong Kong) and in native populations of Central and South America (eg, Peru and Mexico) where it accounts for 5 to 10 percent of all non-Hodgkin lymphoma [3-11]. It is a rare disorder in the United States, Europe, South Asia, the Middle East, and Africa. In the United States, the incidence is highest among Hispanic White Americans and Asian/Pacific Islanders and lowest among Black Americans, non-Hispanic White Americans, and American Indian/Alaska natives [12].

The median age at presentation is 52 years [8]; however, rare cases have been reported in childhood. There is a male predominance of approximately 2:1 [5,8,13,14].

PATHOGENESIS — The pathogenesis of ENKL is poorly understood but is related in part to infection of the tumor cells with Epstein-Barr virus (EBV). In virtually all cases, the tumor cells contain monoclonal episomal EBV genomes and express EBV-encoded small nuclear RNAs (EBERs). Expression of EBV latent membrane protein-1 (LMP-1) by immunohistochemistry has also been described [15].

●p53 overexpression – A high percentage of these tumors overexpress the p53 tumor suppressor protein, which is due to TP53 mutation in a substantial minority of tumors [16-18]. Curiously, the cyclin dependent kinase inhibitor p21, which is a downstream target of p53, is overexpressed in these tumors independent of TP53 mutational status [16]. In most other tumor types, p21 overexpression is linked to wild-type p53 expression, but in this tumor it has been found even with mutant p53 or low p53 expression; it is hypothesized that p21 overexpression may be related to EBV infection.

●Other mutations – Other frequently mutated genes include those encoding components of the JAK/STAT pathway, particularly JAK3 [19,20], suggesting that increased JAK/STAT signaling contributes to the growth and survival of ENKL cells. Mutations in genes encoding RNA helicases (particularly DDX3) and epigenetic regulators have been reported [21]. Other tumor suppressor genes that have been implicated in the pathogenesis of ENKL include PRDM1 (also known as Blimp-1), which lies within a region on chromosome 6 that is frequently deleted in ENKL [22], and FOXO3. One study reported that most tumors had down-regulated PRDM1 and FOXO3, in association with nonsense and missense mutations [23].

●Epigenetic effects – The TP73 gene, which shares structural and functional homology with TP53 and is thought to be a tumor suppressor gene, has been found to be highly methylated in these tumors; less often, the genes that encode the tumor suppressors, p16 (cyclin-dependent kinase inhibitor 2A [CDKN2A]) and p15 (cyclin dependent kinase inhibitor 2B [CDKN2B]) are hypermethylated [24].

CLINICAL FEATURES — 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 (image 1) [5,13,25,26]. Other extranodal sites may be involved either primarily (ie, 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 [8,26-35]. Lymph nodes may be involved secondarily, but are only rarely the primary site of involvement [28]. Bone marrow involvement and B symptoms (ie, fever, night sweats, weight loss) are seen in approximately 10 and 35 percent of patients, respectively [8,14].

As an example, a retrospective analysis of 145 patients with nasal-type NK/T cell lymphoma reported that the majority of patients presented with Ann Arbor stage I (81 percent) or II (17 percent) disease, with nodal involvement being uncommon (17 percent). Systemic B symptoms or an elevated lactate dehydrogenase level were seen in 34 and 46 percent of patients, respectively [14].

Another single institution analysis compared the presentation and clinical outcomes of nasal (181 patients) and extranasal (50 patients) ENKL [26]. When compared with nasal NK/T cell lymphoma, extranasal NK/T cell lymphoma had a slightly different immunophenotype and was more likely to present with stage II or greater disease (56 versus 20 percent), B symptoms (54 versus 37 percent), and impaired performance status (10 versus 3 percent). However, the outcomes were similar for nasal and extranasal NK/T cell lymphoma when matched for stage.

Importantly, approximately 3 percent of ENKL are associated with the hemophagocytic syndrome, an often fatal complication, which may present with high fevers, maculopapular rash, failure to thrive, central nervous system symptoms, hepatosplenomegaly, lymphadenopathy, cytopenias, coagulopathy, abnormal liver function tests, or extremely high serum ferritin levels [8,36-38]. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

Some cases of the aggressive variant of NK cell leukemia/lymphoma may be related to and seen in conjunction with ENKL [39]. (See "Natural killer (NK) cell large granular lymphocyte leukemia".)

PATHOLOGIC FEATURES

Morphologic features

Growth pattern — Involved tissues usually demonstrate extensive ulceration and a diffuse, permeative lymphomatous infiltrate. Mucosal glands, if present, are widely spaced and there is usually prominent coagulative necrosis of both tumor cells and normal tissue [1]. An angiocentric/angiodestructive growth pattern is a characteristic, but not essential, feature that is associated with fibrinoid necrosis of blood vessel walls. Vascular lumina may be occluded by lymphoid cells with varying degrees of cytologic atypia [40], sometimes in association with thrombosis. Mitotic figures are variably plentiful, but usually common.

The polymorphous infiltrate is composed of a mixture of normal-appearing small lymphocytes and atypical lymphoid cells of varying size [28,29], along with plasma cells and occasionally eosinophils and macrophages (picture 1).

Cell morphology — The morphology of the tumor cells in ENKL varies widely. The cells can be of any size, but most commonly are either medium-sized or a mixture of small and large cells. They often have a moderate amount of pale/clear cytoplasm, irregularly folded nuclei, granular chromatin, and inconspicuous or small nucleoli [1]. Azurophilic granules may be seen on touch preps stained with Giemsa.

Immunophenotype — The immunophenotype of ENKL is usually similar to that of a natural killer (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 proteins such as granzyme B, TIA-1, and perforin, and lack surface T cell receptor (TCR) [15,41]. Uncommon cases may express CD4, CD8, and/or CD7 [29,30,42]. The tumor cells may also express CD30, particularly in cases in which large cells predominate, potentially leading to misdiagnosis as anaplastic large cell lymphoma [43].

Genetic features — The TCR and immunoglobulin (Ig) genes are usually germline, but a minor fraction of cases demonstrate clonal rearrangement of TCR genes, suggesting derivation from a cytotoxic T lymphocyte [33]. Clonal Epstein-Barr virus (EBV) genomes are virtually always present [30,31,44]. In situ hybridization for EBV encoded small nuclear RNAs (EBERs) is the preferred method of demonstrating the presence of EBV.

Many genetic abnormalities have been reported, but there is no typical or diagnostic cytogenetic change. The most common cytogenetic abnormality is deletion of chromosome 6q [22,45]. As mentioned above, PRDM1 is one candidate tumor suppressor gene that maps to the deleted region. Genome-wide association studies (GWAS) have implicated single-nucleotide polymorphisms (SNPs) of certain human leukocyte antigen (HLA) genes and IL18RAP in the genetic risk for NKTCL development [46,47].

DIAGNOSIS — The diagnosis of ENKL is made based on the evaluation of a biopsy specimen from the site of involvement, usually in the midfacial area (table 1). Because the morphology of the tumor cells is so variable, it is important to consider this diagnosis in all cases of aggressive extranodal lymphoma, including unusual cases presenting outside of the nasopharynx, particularly when vascular invasion and necrosis are noted. Given the aggressive nature of these tumors the evaluation of suspected cases should be carried out with a sense of urgency, usually with a biopsy performed within one week.

The key diagnostic features are the demonstration of natural killer (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 [1].

As described above, the histology is typically characterized by a polymorphous lymphoid infiltrate that invades the vascular walls, producing fibrinoid necrosis of vessel walls and coagulative necrosis of surrounding tissues. The tumor cells are highly variable in morphology; sometimes small or large cells predominate, but most often there is a mixture of small and large cells. (See 'Morphologic features' above.)

Over 90 percent of cases are of true NK cell origin. These tumors express CD2, cytoplasmic CD3, CD56, and cytotoxic granule proteins, are negative for surface CD3, and have T cell receptor genes in the germline configuration. (See 'Immunophenotype' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of ENKL includes other natural killer (NK) and T cell hematologic malignancies and Epstein-Barr virus (EBV)-associated T cell or NK cell lymphoproliferative disorders, certain subsets of which occur predominately in children (eg, chronic active EBV infection, systemic EBV-positive T cell lymphoma of childhood and hydroa vacciniforme-like lymphoproliferative disorder [2,48]). (See "Infectious mononucleosis", section on 'Chronic active EBV infection'.)

NK cell leukemia — Infrequently, patients with ENKL can have involvement of the bone marrow and peripheral blood resembling that seen in aggressive NK cell leukemia. It is unclear whether these are two distinct pathologic entities or if they merely represent two different clinical presentations (ie, leukemia and lymphoma) of a single entity.

The immunophenotype of aggressive NK cell leukemia is practically identical to that of ENKL. In addition, EBV involvement is common in both entities. However, aggressive NK cell leukemia frequently expresses CD16 (75 percent of cases), while CD16 is typically negative in ENKL [1].

Lymphomatoid granulomatosis — Lymphomatoid granulomatosis is another EBV-positive tumor that appears at extranodal sites and can bear a close histologic resemblance to ENKL. Cases of pulmonary "lymphomatoid granulomatosis" were for a time considered to be part of the spectrum of ENKL. However, the EBV-positive tumor cells in lymphomatoid granulomatosis are of B cell origin and thus express pan-B cell markers such as CD20, while the EBV-positive cells in ENKL are of NK or T cell origin. (See "Pulmonary lymphomatoid granulomatosis", section on 'Pathology'.)

EBV-positive mucocutaneous ulcer — EBV-positive mucocutaneous ulcers are defined by the presence of isolated circumscribed ulcerative lesions, typically occurring in elderly individuals, sometimes in the setting of immunosuppression [49]. The lesions are most common in the oropharynx, but may also occur in the skin or in the gastrointestinal tract. The lesions contain a polymorphous inflammatory infiltrate mixed with scattered EBV-infected B cells, which frequently include cells resembling Hodgkin/Reed-Sternberg cells morphologically and immunophenotypically. The entity is distinguished from Hodgkin lymphoma by its extranodal presentation and benign course, including frequent spontaneous regressions and excellent responses to conservative treatments.

EBV-positive diffuse large B cell lymphoma, NOS — EBV-positive diffuse large B cell lymphoma (DLBCL), not otherwise specified, is a variant of DLBCL that often presents at extranodal sites and may exhibit angioinvasion, angiodestruction, and extensive tissue necrosis. However, unlike ENKL, presentations in the nasopharynx are unusual, the tumor cells are positive for B cell markers (CD20, CD79a), and genotypic studies reveal the presence of clonal immunoglobulin rearrangements. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

Peripheral T cell lymphoma, unspecified — T cell lymphomas that cannot be classified into a specific subtype, are labeled peripheral T cell lymphoma, unspecified. Tumors that express CD3 but do not express CD56 and are negative for EBV and cytotoxic molecules should be diagnosed as peripheral T cell lymphoma, unspecified rather than ENKL. Node-based EBV-positive PTCL are also classified as peripheral T cell lymphoma, unspecified [2]. These monomorphic tumors often present in older adults and lack the angioinvasion and necrosis typical of ENKL. (See "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified".)

Anaplastic large cell lymphoma — Some ENKL tumors are diffusely positive for CD30, and particularly in instances where large cells predominate, such tumors may be misdiagnosed as anaplastic large cell lymphoma (ALCL), ALK-negative. The distinction from ALCL can be made by performing tests for EBV, which is never present in ALCL and virtually always present in ENKL. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma", section on 'Diagnosis'.)

Hepatosplenic T cell lymphoma — Hepatosplenic T cell lymphoma is a neoplasm of mature gamma/delta T cells that infiltrate the sinusoids of the spleen, liver, and bone marrow. The immunophenotype may resemble that seen in ENKL with expression of CD2, CD7, and variable expression of CD56. However, these tumors also express surface CD3 and surface T cell receptors (usually of the gamma/delta type), findings atypical for ENKL. In addition, these tumors do not typically express granzyme B or perforin, which are found in extranodal NK/T cell lymphoma. Isochromosome 7, a genetic aberration that is not seen in ENKL, is present in most cases. (See "Clinical manifestations, pathologic features, and diagnosis of hepatosplenic T cell lymphoma".)

Squamous cell carcinoma — Some cases of ENKL may elicit prominent pseudoepitheliomatous hyperplasia of the overlying mucosal epithelium that can resemble squamous cell carcinoma. While exuberant, the epithelial hyperplasia lacks atypia, whereas the underlying lymphoid infiltrate is usually overtly malignant. Detection of EBV in the lymphoid tumor cells is a helpful finding in unusual cases of ENKL that are comprised mainly of small lymphoid cells and that lack areas of necrosis. (See "Pathology of head and neck neoplasms".)

Nonkeratinizing nasopharyngeal carcinoma — Nonkeratinizing nasopharyngeal carcinoma (NPC) is an epithelial neoplasm arising from the epithelial lining of the nasopharynx that has a similar clinical presentation to ENKL. In addition, both pathologic entities are associated with EBV infection.

Nonkeratinizing NPCs are characterized by a dense lymphoplasmacellular infiltrate containing cohesive nests or scattered tumor cells (picture 2). The neoplastic cells have large nuclei, prominent eosinophilic nucleoli, and scant cytoplasm. When growing in clusters, the cell borders are indistinct, thus giving a syncytial appearance. The tumor sometimes contains numerous infiltrating lymphocytes, primarily T cells, but these cells are morphologically benign. NPC can be distinguished from ENKL by performing immunohistochemical stains for cytokeratin, which are positive in NPC and negative in ENKL. (See "Pathology of head and neck neoplasms".)

NK cell enteropathy — NK cell enteropathy is a proposed clinicopathologic entity characterized by involvement of the gastrointestinal mucosa by an extensive atypical NK cell lymphoproliferative process with an indolent course [50,51]. Gastrointestinal biopsy reveals expansion of the lamina propria by a well-circumscribed but confluent infiltrate. The tumor is comprised of intermediate-sized cells with irregular nuclei, inconspicuous nucleoli, finely clumped chromatin, and a moderate amount of pale cytoplasm. There can be sheets of atypical cells with destruction of the mucosal glands, but necrosis is otherwise absent. There is no epitheliotropism, angiocentricity or angiodestructive growth, and NK cell enteropathy is not EBV-associated. The atypical cells characteristically express CD7, cytoplasmic CD3, TIA-1 and/or Granzyme B, but not CD4, CD5, CD8, CD10, CD20, CD30, PAX-5, CD138, or CD68. The MIB-1/Ki-67 proliferation fraction is low. T cell receptor studies are oligoclonal or polyclonal. The peripheral blood and bone marrow are not involved.

Tumors involving the gastrointestinal tract with EBV positivity and/or a high proliferation fraction are better considered variants of aggressive ENKL than NK cell enteropathy [51].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging".)

SUMMARY

●Extranodal natural killer (NK)/T cell lymphoma, nasal-type (ENKL) is an extranodal lymphoma most common in Asia and Central and South America, which typically presents with localized disease resulting in symptoms of nasal obstruction, epistaxis, and/or a destructive mass involving the nose, sinuses, or palate (image 1). (See 'Epidemiology' above and 'Clinical features' above.)

●Diagnosis is made based on the evaluation of a biopsy specimen from the site of involvement (table 1). The histology is typically characterized by a polymorphous lymphoid infiltrate with highly variable morphology that invades the vascular walls, often producing extensive necrosis. The key diagnostic features are the demonstration of NK/T cell markers on immunophenotyping (typically CD2+, CD56, cytoplasmic CD3+, surface CD3–, CD4+/-, and CD8+/-) and the presence of Epstein-Barr virus (EBV), usually by in situ hybridization for EBV-encoded RNA (EBER). (See 'Diagnosis' above and 'Pathologic features' above.)

●Differential diagnosis includes other NK and T cell hematologic malignancies and EBV-associated T cell or NK cell lymphoproliferative disorders. (See 'Differential diagnosis' above.)