extranodal NK/T-cell lymphoma

Definition: Extranodal NK/T-cell lymphoma, nasal type is a predominately extranodal lymphoma with a cytotoxic phenotype and a strong association with EBV. The upper aerodigestive tract is most commonly involved with other preferential sites including the skin, soft tissue, gastrointestinal tract, and testis. These tumors express CD56, TIA-1, and granzyme B and are positive for EBER. The clinical course is very aggressive. The great majority of such tumors are of NK-cell lineage, although some are of cytotoxic T-cell phenotype.

Park et al. described a series of systemic EBV-positive T-cell lymphoma in immunocompetent elderly patients, which they proposed as a distinct entity related to an underlying dysfunction of the T-cell immunity resulting in a failure to eradicate the EBV infection. These patients usually presented with generalized lymphadenopathy.

Extranodal NK/T-cell lymphoma (ENKTL), nasal type, may be of NK or T-cell origin; however, the proportion of T-ENKTLs and whether they are of αβ or γδ type remains uncertain.

Intestinal ENKTLs were EBV and had significantly more frequent CD30, pSTAT3, and IRF4/MUM1 expression but less frequent CD16 compared with γδ EATL.

Significant adverse prognostic indicators included a primary non-upper aerodigestive tract site, high stage, bone marrow involvement, International Prognostic Index ≥2, lack of radiotherapy, Ki67 >40%, and CD25 expression.

The upper aerodigestive tract ENKTLs of T-cell origin compared with those of presumptive NK origin showed a trend for better survival.

Thus, at least 11% of evaluable ENKTLs are of T-cell origin.

Although T-ENKTLs have phenotypic and some possible clinical differences, they share many similarities with ENKTLs that lack TCR expression and are distinct from intestinal γδ EATL.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is a tumor most frequently seen in the head and neck primarily in the nasal cavity, which is predominantly extranodal of either T cell or natural killer cell lineage.

ENKTL is characterized by Epstein-Barr virus (EBV) infection, necrosis, cytotoxic immunophenotype and angioinvasion.

The tumor is named based on the site where it most frequently occurs, specifically in the upper aerodigestive tract, and it most frequently involves the nasal cavity and/or paranasal sinuses; less often, involvement of the nasopharynx and oral cavity (palate) may occur and in such situations secondary extension from a primary nasal cavity tumor should be excluded.

ENKTL may occur in extra-nasal non-head and neck sites including skin, soft tissue, gastrointestinal tract and testes, and can secondarily involve lymph nodes. The issue relative to nomenclature in lesions originating outside of the nasal cavity remain to be determined.

Since ENKTL is typically extranodal, cases that are primary to a lymph node are still classified as extranodal NK/T-cell lymphoma, nasal type, but there is speculation that they could be grouped with another lymphoma and may represent a distinct lesion.

EBV is consistently present in ENKTL suggesting its critical role for EBV in the pathogenesis of ENKTL. Not only is EBV invariably present, but it is usually type A EBV.

It is well recognized that EBV is in a clonal episomal form producing cytokines including IL-9 and IL-10 which are pro-oncogenic. Peripheral blood of patients with ENKTL contains fragmented EBV-DNA derived from neoplastic cells. The EBV-DNA copy numbers are of prognostic significance and reflect the tumor burden.

Additionally this tumor occurs more commonly in the setting of immunosuppression including organ transplantation. The tumor is found most frequently in people from Asia and in Native Americans from Central and South America, which suggests that there is a racial predisposition to the tumor.

Although the tumor is rare in the United States, the incidence is rising. ENKTL tends to be a disease of adulthood with a mean age of approximately 56 years of age and more commonly involves men as compared to women.

The typical presentation is a destructive midline facial lesion often associated with epistaxis, nasal septal perforation, nasal obstruction, palatal perforation and/or orbital swelling.

ENKTL can also disseminate; regional lymph node involvement is not uncommon. Once a diagnosis is established, bone marrow biopsy is performed as part of disease staging, and can be involved (leukemic phase).

Prognosis

Prognosis is typically poor even though the disease often presents at early stage; outcomes are even worse for extranasal ENKTL.

Poor prognostic indicators for ENKTL include a high international prognostic index or Korean NK/T cell prognostic score, an elevated C-reactive protein, anemia (@<@11 g/dL) or thrombocytopenia, large cells >40% and a proliferative rate by ki-67 greater than 50%.

High serologic levels of plasma EBV-DNA may also represent an adverse prognostic indicator.

Managemenet

Treatment typically consists of radiotherapy with or without multiagent chemotherapy. Radiotherapy may be effective in localized disease, but is often limited in extensive disease.

Platelet-derived growth factor α has been shows to be overexpressed in gene expression profile studies which suggests a possible future role for imatinib therapy.

ENKTL has traditionally been considered an aggressive tumor with a poor prognosis. However, newer treatment protocols such as simultaneous chemotherapy and radiation or l-aspiraginase based treatments such as SMILE (steroid, methotrexate, ifosfamide, l-asparaginase and etopside) have lead to improved outcomes.

Microscopy

The histologic features of ENKTL at low magnification include diffuse effacement of the involved site with associated “geographic” type necrosis.

A broad cytologic spectrum of the lymphoid infiltrate may be seen including cell sizes ranging from small to medium to large. The cellular infiltrate may be overtly cytomorpholgically malignant but in some cases may appear as a mixed inflammatory cell infiltrate without histologic evidence of malignancy. Nuclear shapes can by atypical and chromatin can range from coarse to vesicular with distinct nucleoli. The cells often have azurophilic cytoplasmic granules, best identified on touch preparation slides.
Mitotic figures are readily identified. The cellular infiltrate is associated with coagulative necrosis in approximately 90% of cases.

Further, lymphoid infiltrate is distinctly angiocentric and angiodestructive although these findings may not be easily recognized in limited tissue sampling. When identified angiocentricity including neoplastic cells surrounding blood vessels and angiocentricity includes lesional cells within vascular walls that may include destruction of the blood vessel wall and/or thrombus-like effect with occlusion of the lumen.

Elastin stains and/or vascular markers (e.g., CD31, CD34, Factor 8-related antigen, others) may be used to delineate the blood vessels.

Synopsis

 Diffusely effaced architecture by lymphoid infiltrate.
 Pleomorphic cells with moderate cytoplasm.
 Lesional cells are EBER positive.
 Positive immunostaining for CD2.
 CD56 positivity.
 Granzyme B shows a granular staining pattern.
 The cells were negative for CD20, CD5, CD8 and CD4.

In mucosal sites such as the sinonasal tract there is often surface epithelial ulceration and intact overlying mucosa may show pseudoepitheliomatous hyperplasia. In lymph nodes, ENKTL preferentially involves the paracortical and medullary areas.

Bone marrow can be involved in approximately 10-20% of cases although the infiltrate is usually subtle with an interstitial growth pattern lacking discrete infiltrates

EBER staining is a very useful adjunct in the diagnosis of ENKTL. Lesional cells whether obviously malignant or lacking cytomorphologic features of a malignant cellular infiltrate are EBER positive. Further, EBER staining can be used to locate tumor cells in the bone marrow.

Immunochemistry

There are a variety of cell types in ENKTL. NK cells are the most common; γδ T cells are second most frequent and αβ are the least common.

ENKTLs with a NK-cell lineage typically are positive for CD2, CD56 (+/-), CD94 (lectin type killer receptor) and CD3€ (NK cells express the epsilon chain of CD3 which is cytoplasmic in immunohistochemistry and by flow cytometry), but are negative for CD4, CD8, CD57, and CD5.

CD16 is only found in a minor proportion of cases. 30 ENKTL with a T cell lineage are positive for CD2, CD3, CD5, CD8(+/-), TBET, ETS and loss commonly CD56 (-/+).

ENKTL has an activated cytotoxic phenotype, and cytotoxic markers such as granzyme B and TIA are positive in both the NK and T cell lineages.

CD56 is typically positive in ENKTL, but is most often negative in enteropathy associated T cell lymphoma (EATL) type 1, another T cell lymphoma which is often in the differential diagnosis. EATL type 2 can be more difficult to differentiated from ENKTL and both can be CD56 (+).

EBV latent membrane protein is variably expressed in EATL and usually marks fewer cells than EBER in situ hybridization which is consistently diffusely positive.

Lack of EBV positivity virtually excludes the diagnosis of ENKTL; so the absence of EBV questions the validity of the diagnosis.

Differential diagnosis

In the sinonasal tract, the differential diagnosis includes granulomatosis with polyangiitis [GPA] formerly referred to as Wegener granulomatosis. In contrast to ENKTL, lesional cells of GPA are EBER negative. Further, elevated serologic levels of antineutrophil cytoplasmic antibody (c-ANCA) and/or proteinase 3 (PR3) are raised in active GPA but absent in ENKTL.

Cytogenetics

Molecular changes have been studied in ENKTL which may have diagnostic as well as prognostic implications. Gene expression profiling has shown overexpression of angiogenesis markers and EBV infection markers.

T cell receptor gene rearrangement studies may be routinely used to prove T cell clonality; however, ENKL with s NK cell lineage with not carry TCR gene rearrangement. Isochromosome 7q has also been detected in rare cases of ENKL which proves that isochromosome 7q is not a specific molecular finding for hepatosplenic lymphoma.

Granzyme H expression is high in ENKL as compared to other peripheral T cell lymphomas, and may become a diagnostic marker.

Comparative genomic hybridization studies have documented multiple gains and losses; the most common gain is 2q; the most frequent site of losses are 1p36, 6q16-q27, 4q12, 5q34-q35, 7q21, 9p, 11q22, 12p, 12q, and 15q11.

A variety of gene mutations have been involved involving FAS, β-catenin, KRAS, KIT and TP53 32. Other potential tumor suppressor genes implicated in ENKL include PRMD1, ATG5, AIM1, FOXO3, and HACE1.

References

 http://www.semdiagpath.com/article/S0740-2570(14)00108-7/fulltext

 Extranodal NK/T-cell Lymphoma, Nasal Type, Includes Cases of Natural Killer Cell and αβ, γδ, and αβ/γδ T-cell Origin: A Comprehensive Clinicopathologic and Phenotypic Study. Pongpruttipan T, Sukpanichnant S, Assanasen T, Wannakrairot P, Boonsakan P, Kanoksil W, Kayasut K, Mitarnun W, Khuhapinant A, Bunworasate U, Puavilai T, Bedavanija A, Garcia-Herrera A, Campo E, Cook JR, Choi J, Swerdlow SH. Am J Surg Pathol. 2012 Feb 3. PMID: 22314189