Natural killer-cell malignancies: diagnosis and treatment
1Department of Medicine, University of Hong Kong, Hong Kong, China
Natural killer (NK)-cell malignancies are uncommon diseases.
Previously known as polymorphic reticulosis or angiocentric
T-cell lymphomas, they are classified by the World Health
Organization as NK/T-cell lymphoma, nasal type and aggressive
NK-cell leukemia. They are prevalent in Asia and South
America, but exceptionally rare in western countries. Patho-
logically, NK-cell lymphomas show a polymorphic neoplastic
infiltrate with an angioinvasive and angiodestructive pattern.
Lymphoma cells are characteristically CD2þ, CD56þ and
cytoplasmic CD3eþ. T-cell receptor gene is germline, and
clonal Epstein–Barr virus (EBV) infection is almost invariably.
Clinically, they can be divided into nasal, non-nasal, and
aggressive lymphoma/leukemia subtypes. Most nasal NK-cell
lymphomas present with stage I/II disease, and frontline
radiotherapy is the most important key to successful treatment.
Many stage I/II patients treated with radiotherapy fail systemi-
cally, implying that concomitant chemotherapy may be needed.
Chemotherapy is indicated for advanced nasal NK-cell lympho-
ma, and the non-nasal and aggressive subtypes. However,
treatment results are unsatisfactory. High-dose chemotherapy
with hematopoietic stem cell transplantation may be beneficial
to selected patients. The International Prognostic Index and
presentation EBV DNA load is of prognostic significance and
may be useful in the stratification of patients for various
Leukemia (2005) 19, 2186–2194. doi:10.1038/sj.leu.2403955;
published online 22 September 2005
Keywords: natural killer-cell lymphoma; nasal; non-nasal;
Natural killer (NK) cells are cytolytic cells capable of targeting
tumor cells and bacteria- or virus-infected cells.1Morpholo-
gically, NK cells are lymphoid cells with pale cytoplasm
containing azurophilic granules. Developmentally, NK and
T cells may share a common bipotential T/NK progenitor cell.
Therefore, NK cells express variably T-lineage-associated
antigens, including CD2 and sometimes CD7. They are negative
for surface CD3, but express cytoplasmic CD3 epsiolon (e)
chain. NK cells also express a number of ‘NK-associated’
antigens, including CD16, CD56 and CD57.2CD56 is most
consistently expressed, and has been widely regarded as a
marker for NK cells. However, CD56 is not specific for NK cells,
and can be found on NK-like T-cells, neural and neuroendo-
crine tissues, and occasionally skeletal muscles.3Molecularly,
NK cells have germline T cell receptor (TCR) genes, which is
different from T cells where the TCR genes are rearranged.
Neoplastic disorders of NK cells
In 1992, two groups described independently lymphoid
malignancies that expressed CD56,4,5characterized by a
predominant extranodal distribution and an aggressive course.
However, the putative NK-cell origin of these tumors was not
established initially, because the neoplastic cells were appar-
ently CD3 positive, which led to the diagnosis of a T-cell
malignancy. The problem was resolved when it was realized
that whereas polyclonal anti-CD3 antibodies bound both
surface CD3 and cytoplasmic CD3e, monoclonal anti-CD3
antibodies bound only surface CD3.6Therefore, immunohisto-
chemical analysis with polyclonal anti-CD3 antibodies on
formalin-fixed paraffin-embedded histologic sections cannot
differentiate between T and NK cells (both apparently CD3
positive, T cells for surface CD3; NK cells for cytoplasmic
CD3e). However, on frozen or cryostat sections stained with
monoclonal anti-CD3 antibodies, NK cells can be differentiated
clearly from T cells, with the former negative and the latter
positive for surface CD3.
Classifications of NK-cell lymphomas
The World Health Organization (WHO) classification divides
NK-cell lymphomas into two histologic categories, NK/T-cell
lymphoma, nasal type7and aggressive NK-cell leukemia.8This
is a pathologic classification. In clinical practice, NK-cell
lymphomas can be classified into three categories: nasal, non-
nasal and aggressive lymphoma/leukemia subtypes, each with
different clinical manifestations, treatment approaches and
prognosis (Table 1).9NK-cell lymphomas are predominantly
extranodal, and lymph node involvement at presentation or
subsequently is uncommon.10
Nasal NK-cell lymphoma
Nasal NK-cell lymphomas refer to tumors occurring in the nose
and the upper aerodigestive tract.11–15Males are predominantly
affected, with the median age of presentation in the fifth decade.
The nasal cavity, nasopharynx, paranasal sinuses, tonsils,
hypopharynx and larynx may be involved. Symptoms are local,
including facial swelling, nasal obstruction and bleeding,
proptosis and impairment of extraocular movement. Downward
extension of a nasal tumor may result in destruction of the hard
palate, leading to the highly characteristic midline perforation,
to which the term ‘lethal midline granuloma’ was once applied
Non-nasal NK-cell lymphomas
Non-nasal NK-cell lymphomas may involve any part of the
body.17Males are again predominantly affected, with the
median age of presentation in the fifth decade. Primary sites
include the skin, gastrointestinal tract, salivary glands, spleen
and testis.17Occasional involvements of muscle18and the
uterus19have been reported. Isolated nodal involvement is
Received 15 June 2005; accepted 12 August 2005; published online
22 September 2005
Correspondence: Professor YL Kwong, Department of Medicine,
Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong
Kong, China; Fax: þ852 2 974 1165; E-mail: firstname.lastname@example.org
Leukemia (2005) 19, 2186–2194
& 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00
highly unusual, and such cases must be carefully evaluated to
exclude other CD56-expressing hematolymphoid malignan-
cies.20The diagnosis of non-nasal NK-cell lymphoma requires
the exclusion of nasal involvement at presentation. A nasal
panendoscopy with random biopsies should be performed to
exclude occult involvement.
Aggressive NK-cell lymphoma/leukemia
Aggressive NK-cell lymphoma/leukemia is a catastrophic
disease.21,22Men and women are equally affected, at a younger
median age in the third decade. At presentation, the patient is
typically very ill with significant weight loss, jaundice and high
fever. Lymphadenopathy may be found with hepatospleno-
megaly and sometimes skin infiltration. Severe anemia and
thrombocytopenia are common, due to direct marrow infiltra-
tion or active hemophagocytosis in the marrow and occasion-
ally the peripheral blood.21The white cell count may be
increased due to circulating neoplastic cells. Liver function
derangement and features of disseminated intravascular coagu-
lopathy are frequent. The clinical progression is inexorable
despite treatment. Aggressive NK-cell lymphoma/leukemia is an
extremely malignant neoplasm, with the survival measured
often just in days to weeks.
Clinical patterns and dissemination of NK-cell lymphomas
Nasal and non-nasal NK-cell lymphomas share similar histo-
pathologic features and are grouped together in the WHO
classification.7However, they have sufficiently different clinical
behaviors and treatment responses to be segregated into two
distinct categories. Nasal NK-cell lymphomas are localized. At
presentation, they are usually restricted to the nose and upper
aerodigestive tract, and distant metastases are infrequent.
Marrow involvement occurs in less than 10% of patients.23
Even in terminal cases, most nasal NK-cell lymphomas remain
locally invasive. In contrast, non-nasal NK-cell lymphomas are
often multifocal. Distant dissemination occurs early in the
clinical course.17These different clinical patterns have sig-
nificant implications on the treatment strategies and prognosis.
Interestingly, when nasal NK-cell lymphomas metastasize,
they involve organs that are commonly primary sites of non-
nasal NK-cell lymphomas. This phenomenon may be attributed
to the expression of CD56, a homotypic molecule facilitating
cellular adhesion,3on cells of these organs. Aggressive NK-cell
Clinicopathologic features and treatment of nasal NK-cell lymphoma, non-nasal NK-cell lymphoma, and aggressive NK-cell
Nasal NK-cell lymphomaa
Non-nasal NK-cell lymphomaa
Main sites of
Nasal cavities and paranasal
sinuses, upper aerodigestive
Variable neoplastic cell sizes,
zonal necrosis, anigocentricity,
polymorphic infiltrate of small
lymphocytes, plasma cells,
eosinophils and histiocytes
CD2+, surface CD3?,
cytoplasmic CD3e+, CD7+/?,
Stage I: radiotherapy
Stage III/IV: chemotherapy
Aggressive, median survival
Skin, gastrointestinal tract,
testis, salivary glands, other
organs and soft tissues
Variable cell sizes, necrosis and
Disseminated, liver, spleen,
bone marrow, lymph nodes
Monotonous malignant cells,
cytoplasm contains azurophilic
granules, angiocentricity and
necrosis found in organ
CD2+, surface CD3?,
cytoplasmic CD3e+, CD56+
CD2+, surface CD3?,
cytoplasmic CD3e+, CD56+
OutcomeHighly aggressive, median
survival o4 months
Extremely rapid fatal course,
median survival o2 months
aClassified as NK/T-cell lymphoma, nasal type in the WHO classification.
bClassified as aggressive NK-cell leukemia in the WHO classification.
destruction of the hard palate, leading to a communication between
the nasal and oral cavities.
Nasal NK-cell lymphoma with downward extension and
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