Natural killer cell neoplasms: A distinctive group of highly aggressive lymphomas/leukemias

https://doi.org/10.1016/S0037-1963(03)00136-7Get rights and content

Abstract

Natural killer (NK) cell neoplasms, which include extranodal NK/T-cell lymphoma (nasal and extranasal) and aggressive NK cell leukemia, are generally rare, but they are more common in people of Oriental, Mexican and South American descent. These neoplasms are highly aggressive, and show a strong association with Epstein-Barr virus. Extranodal NK/T-cell lymphoma most commonly affects the nasal cavity and other mucosal sites of the upper aerodigestive tract. Patients present with nasal obstruction or midfacial destruction. Despite the early stage of disease at presentation, overall survival is poor. Patients with the extranasal form of the lymphoma often present with high-stage disease, commonly involving the skin, gastrointestinal tract, testis, and soft tissue, and the prognosis is even worse. Histologically, the lymphoma can show a broad cytologic spectrum, but apoptosis, necrosis, and angioinvasion are common. The most common immunophenotype is CD2+, surface CD3, cytoplasmic CD3+, CD56+. Based on currently available data, treatment of nasal NK/T-cell lymphoma should consist of radiotherapy, with or without multiagent chemotherapy. More research is required to ascertain the role of high-dose chemotherapy with stem cell rescue and that of non-multidrug resistance-related chemotherapeutic agents. Aggressive NK cell leukemia affects younger patients, who present with poor general condition, fever, and disseminated disease; they often die within a short time from systemic disease or complications such as multi-organ failure. The peripheral blood and bone marrow show atypical large granular lymphocytes, which exhibit an immunophenotype similar to that of extranodal NK/T-cell lymphoma. Aggressive NK cell leukemia must be distinguished from T-cell large granular lymphocyte leukemia and indolent NK cell lymphoproliferative disorder, both of which are indolent.

Section snippets

Clinical features and behavior

Extranodal NK/T-cell lymphomas show a predilection for Asians, Mexicans, and South Americans.2, 10, 53, 77 It most commonly involves the nasal cavity, which is the prototype of this form of lymphoma. The median age of patients is 53 years, and the male to female ratio is about 3:1.3, 14

Clinical features and behavior

Aggressive NK cell leukemia represents the leukemic end in the range of NK cell neoplasms, analogous to the acute lymphoblastic leukemia-lymphoblastic lymphoma spectrum and chronic lymphocytic leukemia-small lymphocytic lymphoma spectrum.12, 33 While there are usually easily identified neoplastic cells in the peripheral blood and bone marrow, involvement can be subtle, rendering a distinction from disseminated extranodal NK/T-cell lymphoma difficult. Hypersensitivity to mosquito bites may

References (99)

  • WF Kern et al.

    Neural cell adhesion molecule-positive peripheral T-cell lymphoma: A rare variant with a propensity for unusual sites of involvement

    Blood

    (1992)
  • WS Kim et al.

    CHOP followed by involved field radiation: Is it optimal for localized nasal natural killer/T-cell lymphoma?

    Ann Oncol

    (2001)
  • KI Lei et al.

    Primary nasal and nasopharyngeal lymphomas: A comparative study of clinical presentation and treatment outcome

    Clin Oncol (R Coll Radiol)

    (1999)
  • D Leroux et al.

    CD4(+), CD56(+) DC2 acute leukemia is characterized by recurrent clonal chromosomal changes affecting 6 major targets: A study of 21 cases by the Groupe Francais de Cytogenetique Hematologique

    Blood

    (2002)
  • TP. Loughran

    Clonal diseases of large granular lymphocytes

    Blood

    (1993)
  • CS Ng et al.

    Expression of natural killer cell markers in non-Hodgkin’s lymphomas

    Hum Pathol

    (1987)
  • CS Ng et al.

    CD56+ putative natural killer cell lymphomas: Production of cytolytic effectors and related proteins mediating tumor cell apoptosis?

    Hum Pathol

    (1997)
  • T Petrella et al.

    Nasopharyngeal lymphomas: further evidence for a natural killer cell origin

    Hum Pathol

    (1996)
  • T Rudiger et al.

    Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): Results from the Non-Hodgkin’s Lymphoma Classification Project

    Ann Oncol

    (2002)
  • J Suzumiya et al.

    Expression of adult and fetal natural killer cell markers in sinonasal lymphomas

    Blood

    (1994)
  • A Tefferi et al.

    Chronic natural killer cell lymphocytosis: A descriptive clinical study

    Blood

    (1994)
  • KF. Wong

    Genetic changes in natural killer cell neoplasms

    Leuk Res

    (2002)
  • KF Wong et al.

    CD56 (NKH1)-positive hematolymphoid malignancies: An aggressive neoplasm featuring frequent cutaneous/mucosal involvement, cytoplasmic azurophilic granules, and angiocentricity

    Hum Pathol

    (1992)
  • Y Abe et al.

    Subcutaneous panniculitis by Epstein-Barr virus-infected natural killer (NK) cell proliferation terminating in aggressive subcutaneous NK cell lymphoma

    Am J Hematol

    (2000)
  • DA Arber et al.

    Nasal lymphomas in Peru. High incidence of T-cell immunophenotype and Epstein-Barr virus infection

    Am J Surg Pathol

    (1993)
  • JK. Chan

    Natural killer cell neoplasms

    Anat Pathol

    (1998)
  • JK Chan et al.

    Most nasal/nasopharyngeal lymphomas are peripheral T-cell neoplasms

    Am J Surg Pathol

    (1987)
  • JK Chan et al.

    Aggressive T/natural killer cell lymphoma presenting as testicular tumor

    Cancer

    (1996)
  • JKC Chan et al.

    Blastic NK-cell lymphoma. In Pathology and Genetics, Tumours of Haematopoietic and Lymphoid Tissues. World Health Organization Classification of Tumours

  • JKC Chan et al.

    Extranodal NK/T-cell lymphoma, nasal type. In Pathology and Genetics, Tumours of Haematopoietic and Lymphoid Tissues. World Health Organization Classification of Tumours

  • JKC Chan et al.

    Nasal/nasopharyngeal lymphomas: An immunohistochemical analysis of 57 cases on frozen tissues

    Mod Pathol

    (1993)
  • JKC Chan et al.

    Aggressive NK-cell leukemia. In Pathology and Genetics, Tumours of Haematopoietic and Lymphoid Tissues. World Health Organization Classification of Tumours

  • MM Cheung et al.

    Primary non-Hodgkin’s lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients

    J Clin Oncol

    (1998)
  • MM Cheung et al.

    Early stage nasal NK/T cell lymphoma: Preliminary result of intensifying treatment with concurrent chemo-radiation and high dose chemotherapy

    Ann Oncol

    (2002)
  • K Chinen et al.

    Nasal natural killer cell/t-cell lymphoma showing cellular morphology mimicking normal lymphocytes

    Arch Pathol Lab Med

    (2002)
  • WC Chou et al.

    Clonal disease of natural killer large granular lymphocytes in Taiwan

    Br J Haematol

    (1998)
  • I Cuadra-Garcia et al.

    Sinonasal lymphoma: A clinicopathologic analysis of 58 cases from the Massachusetts General Hospital

    Am J Surg Pathol

    (1999)
  • DF Dukers et al.

    Expression of killer cell inhibitory receptors is restricted to true NK cell lymphomas and a subset of intestinal enteropathy-type T cell lymphomas with a cytotoxic phenotype

    J Clin Pathol

    (2001)
  • KS Elenitoba-Johnson et al.

    Cytotoxic granular protein expression, Epstein-Barr virus strain type, and latent membrane protein-1 oncogene deletions in nasal T- lymphocyte/natural killer cell lymphomas from Mexico

    Mod Pathol

    (1998)
  • W Engellenner et al.

    Large granular lymphocyte leukemia

    Lab Med

    (1991)
  • J Fukuda et al.

    Nasal NK-cell lymphoma

    Rinsho Ketsueki

    (1994)
  • K Gaal et al.

    Sinonasal NK/T-cell lymphomas in the United States

    Am J Surg Pathol

    (2000)
  • JR Goodlad et al.

    Primary soft tissue lymphoma: An analysis of 37 cases

    J Pathol

    (1996)
  • Herling M, Teitell MA, Shen RR, et al: TCL1 Expression in plasmacytoid dendritic cells (DC2) and the related CD4+ CD56+...
  • FC Ho et al.

    Presence of Epstein-Barr virus DNA in nasal lymphomas of B and ‘T’ cell type

    Hematol Oncol

    (1990)
  • N Imamura et al.

    Aggressive natural killer cell leukaemia/lymphoma: Report of four cases and review of the literature. Possible existence of a new clinical entity originating from the third lineage of lymphoid cells

    Br J Haematol

    (1990)
  • S Ishihara et al.

    Hypersensitivity to mosquito bites conceals clonal lymphoproliferation of Epstein-Barr viral DNA-positive natural killer cells

    Jpn J Cancer Res

    (1997)
  • S Ishihara et al.

    Hypersensitivity to mosquito bites is not an allergic disease, but an Epstein-Barr virus-associated lymphoproliferative disease

    Int J Hematol

    (2000)
  • ES Jaffe et al.

    Report of the Workshop on nasal and related extranodal angiocentric T/natural killer cell lymphomas: Definitions, differential diagnosis, and epidemiology

    Am J Surg Pathol

    (1996)
  • Cited by (128)

    • EBV–Associated Lymphoproliferative Disorders: Update in Classification

      2019, Surgical Pathology Clinics
      Citation Excerpt :

      This hypothesis is mainly based on the similar ethnic background, morphologic picture, immunophenotype, strong EBV association, and genotype (lack of T-cell receptor gene rearrangements).135 At present, the most accepted differentiating features between the two entities are that aggressive NK-cell leukemia often presents at a younger age (almost a decade younger, with a median age of 40 years), shows B symptoms, has more frequent hepatosplenic and bone marrow involvement, has a lower frequency of cutaneous involvement and more frequent expression of CD16 (positive in 75% of cases), and usually disseminates early in presentation.136–138 Moreover, an array-based comparative genomic hybridization study has reported significance differences in genetic changes between the two disorders, in which 7p−, 17p−, and 1q+ are more frequent in aggressive NK-cell leukemia, whereas 6q− is more common in nasal NK-cell lymphoma.139

    • Malignant Neoplasms of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx

      2019, Head and Neck Pathology: A Volume in the Series: Foundations in Diagnostic Pathology
    • CD21-independent Epstein-Barr virus entry into NK cells

      2018, Cellular Immunology
      Citation Excerpt :

      Epstein-Barr virus (EBV), a member of the γ-herpesvirus family, is one of the most common viruses and persists in a majority of humans as a life-long, asymptomatic infection within B lymphocytes [1]. Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTCL) is a rare EBV-associated non-Hodgkin lymphoma, which affects the nasal cavity [3] and upper aerodigestive tract [4] and is a major subset of NK cell, or more rarely T-cell, neoplasms [2]. The transforming properties of EBV and its role in the pathogenesis of a range of B cell malignancies are well established.

    • Diagnostic Pathology: Blood and Bone Marrow

      2018, Diagnostic Pathology: Blood and Bone Marrow
    • Flow Cytometric Principles in Hematopathology

      2018, Hematopathology: A Volume in the Series: Foundations in Diagnostic Pathology
    View all citing articles on Scopus
    NO LABEL

    *Address correspondence to Dr Michael M.C. Cheung, Department of Clinical Oncology, Room 1116, 11/F, Block R, Queen Elizabeth Hospital, Gascoigne Road, Kowloon, Hong Kong

    View full text