This neoplasm is rare in western countries, but prevalent in Asia (China, Japan, Korea, and Southeast Asia),^5,6,7,8 South America (México, Peru, Brazil),^9,10,11 and Central America, suggesting that ethnic background (i.e., genetic risk factors) may have a role in the pathogenesis of these lymphomas.^12,13 Occasional case series have also been reported from Europe and North America.^14,15 It is more common in males, with a male-to-female ratio of 2:1, and usually affects middle-age adults, with a median age of 49 to 53 years.³

There is a very strong evidence of a pathogenic association between EBV infection and ENKTL. The pattern of viral latency is of type II, being more frequent than type I. The type II latency pattern includes the expression of the EBV nuclear antigen 1 (EBNA-1) and latent membrane protein 1 (LMP-1), while the EBNA-2 is negative. EBV-associated messenger RNA (EBER) is invariably positive in all latency patterns.^{13,16,17,18,19} The EBV is present in a clonal episomal form.^12,13,20,21 Gene expression profiling has shown patterns different from normal NK cells, and several oncogenic pathways are activated including Notch-1, Wnt, JAK/STAT, AKT, and nuclear factor-κB.²² Most studies have also shown different subtypes of EBV associated with the ENKTL in Asia (subtype A) when compared to western countries, including South and Central America (subtype B).^10,13,23,24

Bearing in mind that many ENKTLs spread to the skin, a strict definition of CNKTL requires absence of nasopharyngeal involvement as the primary source of the tumor. Often, it is necessary to undertake comprehensive reviews of the nasal and nasopharyngeal regions using positron emission tomography/computed tomography (PET/CT).^25,26,27

CNKTL usually presents as erythematous plaques, nodules, or as multiple tumors, often with hemorrhage and ulceration, preferentially on the face, trunk, and extremities^2,28,29,30 (Fig. 19-1). Some cutaneous lesions can mimic cellulitis or granulomatous panniculitis.³¹ Approximately, 40% of the cases have evidence of extracutaneous dissemination at diagnosis, 60% have widespread lesions, and 20% have locoregional involvement.^29,30 Systemic symptoms such as fever, malaise, and weight loss may be present, and some cases are accompanied by a hemophagocytic syndrome.^2,32

The median survival for CNKTL is about 15 months. Patients with extracutaneous disease at presentation have a shorter survival as compared with those without extracutaneous involvement. Usually, CNKTL has a less aggressive clinical course and better outcomes when compared with the ENKTL with cutaneous dissemination.³⁰ Age, gender, extent of cutaneous involvement, and initial response to therapy do not seem to have an effect on survival. Moreover, patients with coexpression of CD30 tend to have a more favorable outcome.³³ CD38 expression in ENKTL correlates with a poor outcome, indicating the potential role of this epitope as a therapeutic target.³⁴ Another prognostic marker for ENKTL is circulating plasma EBV-DNA, which is derived from apoptotic and necrotic cells, thus serving as a marker of tumor load.³⁵ Other routine histopathologic parameters have no prognostic impact.^4,10