Aggressive NK-cell leukemia is a disease with an aggressive, systemic proliferation of

natural killer cells Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...

(NK cells) and a rapidly declining clinical course. It is also called ''aggressive NK-cell lymphoma''.

Signs and symptoms

Patients usually present with constitutional symptoms ( malaise,

weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat ( adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other co ...

, fatigue), and

hepatosplenomegaly Hepatosplenomegaly (commonly abbreviated HSM) is the simultaneous enlargement of both the liver (hepatomegaly) and the spleen (splenomegaly). Hepatosplenomegaly can occur as the result of acute viral hepatitis, infectious mononucleosis, and his ...

is commonly found on physical exam. Lymphadenopathy is also found to a lesser extent. Due to the aggressive nature of the disease, patients may initially present at a more advanced stage, with coagulopathies,

hemophagocytic syndrome Hemophagocytic lymphohistiocytosis (HLH), also known as haemophagocytic lymphohistiocytosis (British spelling), and hemophagocytic or haemophagocytic syndrome, is an uncommon hematologic disorder seen more often in children than in adults. It is a ...

, and

multi-organ failure Multiple organ dysfunction syndrome (MODS) is altered organ function in an acutely ill patient requiring medical intervention to achieve homeostasis. Although Irwin and Rippe cautioned in 2005 that the use of "multiple organ failure" or "multisy ...

. Rarely, individuals who have an aggressive NK cell lymphoma that is associated with latent infection with the Epstein-Barr virus (see next section) present with or develop extensive allergic reactions to mosquito bites. The symptoms of these reactions range from a greatly enlarged bite site that may be painful and involve necrosis to systemic symptoms (e.g. fever, swollen lymph nodes, abdominal pain, and diarrhea), or, in extremely rare cases, to life-threatening

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the foll ...

Cause

This disease has a strong association with the

Epstein–Barr virus The Epstein–Barr virus (EBV), formally called ''Human gammaherpesvirus 4'', is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus. It is b ...

(EBV), but the true pathogenesis of this disease has yet to be described. The cell of origin is believed to be an

NK cell Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...

. Blastoid NK cell lymphoma appears to be a different entity and shows no association with EBV.

Sites of involvement

This disease is typically found and diagnosed in peripheral

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...

, and while it can involve any organ, it is usually found in the

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

, and bone marrow.

Diagnosis

Leukemic cells are invariably present in samples of peripheral

to a variable extent.

Pancytopenia Pancytopenia is a medical condition in which there is significant reduction in the number of almost all blood cells (red blood cells, white blood cells, platelets, monocytes, lymphocytes, etc.). If only two parameters from the complete blood coun ...

(

anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...

, neutropenia,

thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...

) is commonly seen as well.

Peripheral blood

The leukemic cells have a diameter mildly greater than a large granular lymphocyte (LGL) and have azurophilic granules and nucleoli of varying prominence. Nuclei may be irregular and hyperchromatic.

Bone marrow

Bone marrow involvement runs the spectrum between an inconspicuous infiltrate to extensive marrow replacement by leukemic cells. Reactive

histiocytes A histiocyte is a vertebrate cell that is part of the mononuclear phagocyte system (also known as the reticuloendothelial system or lymphoreticular system). The mononuclear phagocytic system is part of the organism's immune system. The histiocyt ...

displaying

hemophagocytosis Hemophagocytosis is phagocytosis by histiocytes of erythrocytes, leukocytes, platelets, and their precursors in bone marrow and other tissues. It is part of the presentation of hemophagocytic lymphohistiocytosis Hemophagocytic lymphohistiocyto ...

can be seen interspersed in the

neoplastic A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

infiltrate.

Other organs

Leukemic involvement of organs is typically destructive on tissue sections with necrosis and possibly angioinvasion, and the monotonous infiltrate may be diffuse or patchy.

Immunophenotype

The immunophenotype of this disease is the same as extranodal NK/T-cell lymphoma, nasal type and is shown in the table below.

CD11b Integrin alpha M (ITGAM) is one protein subunit that forms heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as ''macrophage-1 antigen'' (Mac-1) or '' complement receptor 3'' (CR3). ITGAM is also known as CR3A, and cluster of dif ...

and

CD16 CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRI ...

show variable expression.

Genetic findings

Due to the NK lineage, clonal rearrangements of

lymphoid The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid o ...

(T cell receptor; B cell receptor) genes are not seen. The genome of the Epstein Barr virus (EBV) is detected in many cases, along with a variety of chromosomal abnormalities.

Treatment

Currently Aggressive NK-cell leukemia, being a subtype of PTCL, is treated similarly to B-cell lymphomas. However, in recent years, scientists have developed techniques to better recognize the different types of lymphomas, such as PTCL. It is now understood that PTCL behaves differently from B-cell lymphomas and therapies are being developed that specifically target these types of lymphoma. Currently, however, there are no therapies approved by the

U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) specifically for PTCL.

Anthracycline Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from ''Streptomyces'' bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder canc ...

-containing

chemotherapy regimens A chemotherapy regimen is a regimen for chemotherapy, defining the drugs to be used, their dosage, the frequency and duration of treatments, and other considerations. In modern oncology, many regimens combine several chemotherapy drugs in combinat ...

are commonly offered as the initial therapy. Some patients may receive a

stem cell transplant Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...

.d'Amore F, et al. ''Blood.'' 2006;108:A401 Novel approaches to the treatment of PTCL in the relapsed or refractory setting are under investigation.

Epidemiology

This rare form of leukemia is more common among Asians in comparison to other ethnic groups. It is typically diagnosed in adolescents and young adults, with a slight predominance in males.

Research directions

Pralatrexate Pralatrexate, sold under the brand name Folotyn, is a medication used for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). Pralatrexate was approved for medical use in the United States in September 2009, as the first t ...

is one compound currently under investigations for the treatment of PTCL.

References

External links

{{Hematological malignancy histology Acute lymphocytic leukemia Epstein–Barr virus–associated diseases Rare cancers