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Page 2 of 14 Fujimoto et al. J Cancer Metastasis Treat 2021;7:66 https://dx.doi.org/10.20517/2394-4722.2021.157

[1]
ENKL and ANKL are strongly associated with Epstein-Barr virus (EBV) . The geographic distribution of
ENKL is distinctive, with a particularly high prevalence in East Asia and South America. ENKL corresponds
to approximately 2%-11% of cases among all lymphoma subtypes in East Asian countries, whereas the
[2-4]
prevalence is less than 1% in the United States and Europe . Although the distribution and incidence of
ANKL are unclear due to its rarity, the prevalence is approximately one-sixth that of ENKL, accounting for
[5]
fewer than 1% of cases among all malignant lymphomas . ENKL is distinct from other lymphomas based
on its unique characteristics, comprising the dominant involvement of the nasal cavity and nasopharynx.
The majority of ENKL cases are limited to a location around the nose or upper aerodigestive tract,
presenting with typical symptoms of nasal obstruction, epistaxis, or rhinorrhea. In contrast, ANKL is
prevalent in the peripheral blood, bone marrow, liver, and spleen. Most patients suffer general symptoms,
such as fever, general malaise, and loss of appetite. Clinical courses of advanced-stage ENKL and ANKL are
very aggressive, often leading to disseminated intravascular coagulation and multiorgan dysfunction, thus
resulting in a poor prognosis over the past decade. Recently, with an increasing understanding of the
molecular pathogenesis of NK cell neoplasms, novel treatment strategies including targeted agents are
expected to improve survival. In this review, we highlight recent clinical findings for ENKL and ANKL and
discuss future prospects.

CLINICAL CHARACTERISTICS OF NK/T CELL LYMPHOMA/LEUKEMIA
The annual incidence of ENKL varies by ethnicity and geographically from 0.06 in the United States to 0.25
in Hong Kong per 100,000 population . ENKL predominantly occurs in middle-aged individuals with a
[3]
median age of 52-58 years . The incidence is 1.5 times higher in males. Because ENKL commonly
[5-8]
develops in extranodal sites and approximately 10% of ENKL cases are derived from γδ or cytotoxic T
cells , the disease is termed extranodal NK/T cell lymphoma in the World Health Organization (WHO)
[9]
classification. The nasal or paranasal cavities and the upper aerodigestive tract are involved in more than
[5]
80% of ENKL cases, with approximately 70% of these being in a limited stage at diagnosis . The patient’s
initial complaints are generally focal symptoms such as nasal obstruction, epistaxis, and rhinorrhea. In
contrast, the remaining cases develop in extra-nasal sites such as the skin, gastrointestinal tract, lung, or
other uncommon organs . Approximately 60% of cases with an extra-nasal origin are at an advanced stage
[5,7]
at diagnosis. Because ENKL develops predominantly in extranodal sites, stage III cases are rare, occurring in
fewer than 5% of all cases. Therefore, most cases in advanced stage are diagnosed as stage IV. These cases
follow an aggressive clinical course with hemophagocytic syndrome and/or disseminated intravascular
coagulation.

ANKL is a rare leukemic form of NK cell neoplasms, which has been reported mainly in East Asian
countries such as Japan, China, or South Korea. The incidence is 2-3 times higher in males. ANKL
progresses very rapidly, and its very aggressive clinical course is reflected by its name, aggressive NK-cell
leukemia . The median overall survival (OS) of ANKL is only a few months after diagnosis, which is the
[10]
worst prognosis among all lymphoma subtypes . Interestingly, however, a subset of ANKL shows a
[11]
subacute clinical course. These subacute-type patients demonstrate female predominance and better
prognosis with a median OS of more than six months. The median age for ANKL development is 40-42
years old, which is more than 10 years younger than that of ENKL, but it is also distributed in an elderly
population, older than 70 years of age [5,12] . Although most ANKL cases develop de novo, there are some cases
that originate from EBV-associated T/NK lymphoproliferative disease, including chronic active EBV
[13]
infection, which generally develops in a younger population . Unlike ENKL, the clinical symptoms of
ANKL are non-specific, including fever, general malaise, and loss of appetite. Most patients have
hepatomegaly and splenomegaly; thus, increased levels of lactate dehydrogenase and liver enzymes are
commonly observed. Therefore, the accurate diagnosis of ANKL is often difficult, and a postmortem