Page 21 - Read Online

Fujimoto et al. J Cancer Metastasis Treat 2021;7:66 https://dx.doi.org/10.20517/2394-4722.2021.157 Page 3 of 14

diagnosis is sometimes made after an inaccurate diagnosis of acute hepatitis. Complete blood counts show
pancytopenia, and the morphology of leukemic cells varies widely, from normal large granular lymphocyte
to lymphoid cells with atypical nuclei and a prominent nucleolus. Occasionally, the percentage of tumor
cells in the bone marrow and peripheral blood is much lower than that in acute myeloid or lymphoblastic
leukemia, with median percentages of 22% and 8%, respectively . Therefore, it is important to consider
[12]
ANKL as a differential diagnosis particularly in cases with fever of unknown origin, hepatosplenomegaly, or
liver dysfunction.

[1]
The detection of EBV is required to make a diagnosis of ENKL based on the current WHO classification ,
whereas this is not mandated for ANKL since approximately 10%-15% of ANKL cases are negative for
EBV [12,14] . The differences in clinical course and prognosis between ANKL patients with and without EBV
infection are also controversial [12,14,15] .

PROGNOSIS AND PROGNOSTIC MODELS
Several recent reports show that the prognosis of limited-stage ENKL patients has been improved through
the introduction of several effective treatments in the past decade. However, the prognosis of advanced-
stage ENKL patients is still unsatisfactory [7,8,16] . The patients with limited-stage ENKL have a significantly
better prognosis than those with advanced-stage ENKL . In the largest retrospective study of 358 ENKL
[7]
patients, the five-year OS and progression-free survival (PFS) of limited-stage ENKL patients were 68% and
56%, respectively. In addition, the prognosis was significantly better for the limited-stage ENKL patients
treated between 2010 and 2013 than for those treated between 2000 and 2009 (five-year OS of 79% and 63%,
respectively) . One of the reasons for this survival improvement is that the rate of limited-stage patients
[7]
treated with effective chemoradiotherapies has increased . More recently, the prognosis of limited-stage
[16]
ENKL, when achieving event-free survival at 24 months after diagnosis, was demonstrated to be almost
equivalent to that of the age- and sex-matched general population . In contrast, the prognosis of advanced-
[17]
stage ENKL is still poor with five-year OS and PFS values of 24% and 16%, respectively . Although the
[7]
introduction of L-asparaginase (L-asp)-containing chemotherapy has improved the OS, significant
[16]
improvements in clinical practice have not been obtained yet .

The most popular prognostic model for ENKL is the prognostic index of NK lymphoma (PINK) . This
[18]
model was developed to predict the prognosis for treatment-naïve ENKL patients who received non-
anthracycline-based chemotherapies with curative intent. Based on four prognostic factors, including age
older than 60 years, stage III or IV, distant lymph-node involvement, and non-nasal type disease, patients
are stratified into low risk (0), intermediate risk (1), and high risk (2-4) categories, with estimated three-year
OS of 81%, 62%, and 25%, respectively. PINK-E, a prognostic model including EBV-DNA data on PINK,
also links risk factors and OS. The international prognostic index and NK/T cell lymphoma prognostic
index, previously developed prognostic models, were based on patient data of the anthracycline era, and
these do not provide an accurate prognosis for patients receiving recent non-anthracycline-based
chemotherapies [7,19] .

The prognosis of ENKL differs by the site of origin, specifically nasal or extranasal. The prognosis of
patients with an extranasal origin is significantly worse than that of patients with a nasal origin based on
several studies . The largest prospective cohort study of ENKL patients, from the International T cell
[6,8]
Project, showed an OS at five years of 54% in patients with nasal origin and 34% in those with extranasal
origin (log-rank P = 0.019) . However, the impact of the site of disease origin, nasal or extranasal, on OS is
[8]
controversial. Because the percentage of advanced stage disease is generally higher in patients with
extranasal origin than in those with nasal origin, the disease stage could be a confounding factor when