ENKL is rare in the United States and Europe and among those of European descent (<1% of NHL). In contrast, the disease is more prevalent in East Asian countries as well as among Native American populations in Mexico and South and Central America (up to 20% of NHL). It occurs most often in adults with a male predominance.^5,6

The very strong association of ENKL with EBV infection irrespective of the patient’s origin suggests a probable pathogenic role of the virus. The EBV is present in a clonal episomal form with type II latency pattern (EBV nuclear antigen [EBNA]-1+, EBNA-2−, latent membrane protein [LMP]-1+), and it commonly shows a 30-bp deletion in the gene encoding LMP-1.⁷ Most studies show that EBV is typically subtype A in Asia and subtype B in Western countries.^8,9 Extranodal NK/T-cell lymphomas can occur in the setting of immunosuppression, including following hematopoietic stem cell transplantation. A low frequency of HLA-A*0201 allele has been reported in patients with ENKL,¹⁰ suggesting that immune surveillance, likely associated with EBV infection, is important in the pathogenesis of the disease.

ENKL characteristically has an extranodal presentation mostly in the upper aerodigestive tract including the nasal cavity, nasopharynx, paranasal sinuses, and palate. However, some cases show an extranasal presentation. Lymph nodes can also be involved. Patients present with symptoms associated with local tumor infiltration. Typical nasal-type ENKL may show localized disease early on but eventually may disseminate rapidly to various extranasal sites including the skin, GI tract, testis, or cervical lymph nodes. Involvement of these sites may be associated with ulceration, perforation, and symptoms associated with a mass lesion. Systemic symptoms (fever, weight loss, malaise, and night sweats) can be present. ENKL may also be associated with the hemophagocytic syndrome.¹¹

Historically, the prognosis is generally poor, although initial response to therapy is variable. Some patients respond to therapy and can achieve complete remission, whereas others die of disseminated disease despite aggressive therapy. The survival rate is 30% to 40%,^12,13 but in recent years it has improved with more intensive therapy including upfront radiotherapy and SMILE (dexamethaSone, Methotrexate, Ifosfamide, L-asparaginase, and Etoposide) regimen.¹⁴ Unfavorable prognostic factors include advanced stage (III or IV), bone marrow (BM) or skin involvement, and high levels of EBV DNA in the serum.^12,15 Although the neoplastic cells of ENKL can range from small mature-appearing lymphocytes to large transformed cells, the prognostic importance of cytologic grade is unclear.

Histologic features of ENKL are similar irrespective of the site of involvement and characteristically include an angiocentric and angiodestructive growth pattern with coagulative necrosis, admixed apoptotic bodies, and fibrinoid change in blood vessels even in the absence of angioinvasion (Fig. 24-1). Mucosal sites may show florid pseudoepitheliomatous hyperplasia of the overlying epithelium and/or ulceration. The mucosal glands often become widely spaced or lost. The neoplastic infiltrate is composed of atypical lymphoid cells that may be small or medium sized to large or anaplastic, but in most cases the lymphoma is composed of medium-sized cells or a mixture of small and large cells. The chromatin is typically granular although it may have a vesicular appearance in very large cells. Nucleoli are typically small and inconspicuous. Mitotic figures may be frequent, and the cells often have azurophilic cytoplasmic granules that appear ultrastructurally as electron-dense membrane-bound granules. Admixed small lymphocytes, histiocytes, and some granulocytes are often present in the background.^3,16

ENKL is thought most commonly to derive from NK cells and less commonly from cytotoxic T cells (Figs. 24-2, 24-3 and 24-4). Consistent with this is the fact that most cases show expression of NK-associated antigens including CD2, CD56, and cytolytic granules (granzyme B, TIA1, and perforin). Except for the minority of cases derived from T cells, ENKL will be negative for surface CD3 expression yet positive for cytoplasmic CD3 subunits including CD3ε and CD3ζ. As such, ENKL will be positive for CD3 when using polyclonal anti-CD3 antibodies for immunohistochemistry (IHC). ENKL is also typically positive for CD43, CD45RO, HLA-DR, CD25, and FAS (CD95) and negative for CD4, CD5, CD8, TCRδ, βF1, CD16, and CD57.^7,17 In situ hybridization studies for EBV-encoded RNA (EBER) are routinely used in clinical practice to confirm EBV infection.

The TCR and immunoglobulin heavy chain (IGH) genes are in germline configurations in ENKL derived from NK cells. No specific genetic mutations have been identified, although del(6)(q21q25) or i(6)(p10) are common chromosomal abnormalities. Aberrant methylation of promoter CpG regions of multiple genes, in particular p73, has been reported.¹⁸

ENKL in the skin can represent either primary cutaneous disease (20% of primary cutaneous lymphoma in South Korea⁸) (see Chapter 19) or cutaneous involvement by systemic ENKL. There appear to be no major clinical, epidemiologic, or histologic differences between primary and secondary cutaneous disease, although patients with ENKL that is restricted to the skin appear to have a better prognosis and response to therapy.^19,20 In patients with nasal-type ENKL and secondary cutaneous involvement, poor survival is associated with a high international prognostic index (IPI) score.^12,19,20,21 Cutaneous involvement by systemic ENKL occurs in ∼10% of patients and may present as multiple erythematous maculopapular lesions, cellulitis, abscess-like swelling, subcutaneous nodules, or ulceration.^11,19,22 Lesions are most commonly distributed throughout the extremities and trunk (especially the lower extremities).¹⁹ The diagnosis relies on recognizing the typical histologic and immunophenotypic features described above for nasal-type ENKL including detection of EBER by in situ hybridization analysis (Fig. 24-1).