NK-Cell Lymphomas of the Head and Neck

Updated: Jan 12, 2016
  • Author: Benjamin Daniel Liess, MD; Chief Editor: Arlen D Meyers, MD, MBA  more...
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Overview

Background

Natural killer (NK)-cell lymphoma is a type of non-Hodgkin lymphoma (NHL). Most NHLs (90%) are of B-cell origin. In the past, the rarity of non–B-cell malignancies and their similar morphologic findings, coupled with the unavailability of cell markers, made it impossible to establish definitive classifications of subtypes of non–B-cell NHL.

This lack of knowledge also prevented clinicians from gathering meaningful information about the natural history of the disease and its prognosis. The unavailability of this information is demonstrated in previous classification systems, including the Lukes-Collins, Kiel, and Working Formulation systems, which did not identify subclasses of NK/T-cell malignancies.

Advances in tumor cell biology have led to the ability to subclassify NHL via the World Health Organization (WHO) classification of lymphomas (see below). This terminology will likely become more precise as our ability to genetically characterize these tumors improves. [1] Previous terms for NK-cell malignancies and other forms of non–B-cell NHL included lethal midline granuloma, angiocentric lymphoma, malignant granuloma, malignant midline reticulosis, and polymorphic reticulosis. These terms were based on clinical and pathologic characteristics of the diseases encountered.

Controversy still exists over the normal counterpart of NK-cell lymphoma. Whether NK-cell lymphoma represents the presence of a true NK cell or merely the presence of a T cell with abnormal cell markers is under debate. In the absence of unequivocal proof of the exact lineage of NK-cell lymphoma, many investigators prefer to use the term NK/T-cell lymphoma (NKTCL) when classifying this condition. Further understanding of its development and identification of more specific cell markers of NK and T cells will likely resolve this controversy in the future.

The peripheral T- and NK-cell lymphomas classified by the WHO have many subclasses (see below). The subgroupings, which primarily involve the head and neck region, include the nasal and nasal-type extranodal NKTCLs. The term extranodal is used because these forms of malignancies are found outside of the traditional lymph node groupings.

The nasal and nasal-type NKTCLs have distinct presentations and prognoses, and they are believed to have different pathogeneses. Otolaryngologists should understand the importance of differentiating NKTCL from other similar pathologic entities found in the head and neck region; the prognoses differ substantially.

World Health Organization classification of lymphomas

In the WHO lymphoma classification, B-cell neoplasms include the following:

  • Precursor B-lymphoblastic leukemia/lymphoma
  • Chronic lymphocytic leukemia/small lymphocytic lymphoma
  • Lymphoplasmacytic lymphoma
  • Plasma cell myeloma
  • Extraosseous plasmacytoma
  • Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)
  • Follicular lymphoma
  • Mantle cell lymphoma
  • Diffuse large B-cell lymphoma
  • Intravascular large B-cell lymphoma

B-cell proliferations of uncertain malignant potential include the following:

  • Lymphomatoid granulomatosis
  • Posttransplant lymphoproliferative disorder, polymorphic

T-cell and NK-cell neoplasms include the following:

  • Precursor T-lymphoblastic leukemia/lymphoma
  • Blastic NK-cell lymphoma
  • Adult T-cell leukemia/lymphoma
  • Extranodal NKTCL, nasal type
  • Subcutaneous panniculitislike T-cell lymphoma
  • Mycosis fungoides
  • Sézary syndrome
  • Primary cutaneous anaplastic large cell lymphoma
  • Peripheral T-cell lymphoma
  • Angioimmunoblastic T-cell lymphoma
  • Anaplastic large-cell lymphoma

T-cell proliferations of uncertain malignant potential include the following:

  • Lymphomatoid papulosis
  • Hodgkin lymphoma
  • Histiocytic and dendritic-cell neoplasms
  • Mastocytosis
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Pathophysiology

Extranodal NKTCL manifests in the nasal cavity. Patients with this type tend to have earlier disease (stage I). However, later-stage presentations are observed, and the stage at presentation has an impact on the survival rate. Nasal NKTCLs are almost always (>95% of cases) associated with Epstein-Barr virus (EBV), irrespective of the ethnicity of the patient. The exact mechanism of malignant transformation via EBV has not been clearly elucidated. [2]

Extranodal nasal-type NKTCL demonstrates a predilection for the nasopharynx (see the image below), palate, skin, soft tissues, orbit, gastrointestinal (GI) tract, and testes. Secondary lymph nodes may be involved in some cases; a disseminated leukemic picture is even possible. Lymphomas that manifest outside of the nose have a strong association with EBV in Asian patients, but this strong association is not present in whites.

Coronal (left) and axial (right) CT scans of the s Coronal (left) and axial (right) CT scans of the sinus reveal severe pansinusitis with abnormal nasopharyngeal thickening, right facial edema and right temporal bone opacification.

The pattern of involvement of the extranasal sites has been hypothesized to be related to the marker CD56. CD56 represents the neural cell adhesion molecule (NCAM) that has been shown to have homophilic binding properties. With the skin, GI tract, and testes expressing the CD56 marker in large amounts, the neoplastic cells travel to these areas and set up foci of disease. The skin is the most common site of dissemination in NKTCL.

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Etiology

Risk factors for NKTCL are as follows:

  • Inherited immunodeficiencies – Klinefelter syndrome, Chédiak-Higashi syndrome, ataxia telangiectasia syndrome, Wiskott-Aldrich syndrome, and common variable immunodeficiency disease
  • Acquired immunodeficiency diseases – Iatrogenic immunosuppression, HIV-1 infection, and acquired hypogammaglobulinemia
  • Autoimmune disease – Sjögren syndrome, celiac sprue, rheumatoid arthritis, and systemic lupus erythematosus
  • Chemical or drug exposures – Phenytoin, dioxin, phenoxyl herbicides, irradiation, and prior chemotherapy or radiotherapy
  • Association with infectious agents – EBV, human T-cell leukemia/lymphoma virus-I, and ataxia telangiectasia syndrome
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Epidemiology

NKTCL is very rare in whites; its prevalence is significantly higher in people of Asian descent. In Western populations, the prevalence of nasal lymphomas is estimated at 0.17-1.5% of all NHLs, 45% of which are thought to be NK-/T-cell in origin. Worldwide, NKTCL has a low prevalence, but it is much more prevalent in Asia, Mexico, and Central and South America. [3, 4] Reported rates of nasal lymphoma in Hong Kong and South America range from 2.6% to 8% of all NHLs, of which 45% are thought to represent NKTCL.

Patients with NKTCL commonly present in their sixth decade of life, which is almost a decade younger than the age at which people with B-cell neoplasms present. However, the disease has been seen in both geriatric and pediatric populations. [5, 6] Men are more commonly affected with the disease than women, with a male-to-female ratio of almost 3:1. [5, 6, 4]

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Prognosis

Compared with other subtypes of lymphoma found in the head and neck region, NKTCL carries a much higher mortality and responds less well to traditional chemotherapy and radiotherapy regimens. [7] Overall, median survival time is reported as 12.5 months; survival time for patients who present with a disseminated leukemic picture is reported to be less than 6 months. A complete response to primary treatment is reported in 56% of patients. Overall, the 2-year survival rate is 45%, and the 2-year disease-free survival (DFS) rate is reported at 31%.

The poor survival rates and low rates of response to treatment are theorized to be secondary to the CD56 cell marker and the presence of a multidrug resistance (P-glycoprotein–positive) phenotype. CD56 is thought to facilitate tumor cell dissemination by virtue of its binding properties.

A study by Zhang et al indicated that higher levels of myeloid-derived suppressor cells (MDSCs), specifically, HLA-DR-CD33+CD11b+ MDSCs and CD14+ monocytic MDSCs, independently predict poor disease-free and overall survival in patients with extranodal NKTL. The MDSCs were found to suppress T-cell proliferation in these patients. [8]

NKTCLs have a higher local relapse rate (21.4%) than do either T-cell lymphomas presenting in the nasopharynx (5%) or B-cell lymphomas presenting in the nasopharynx (0%). Fewer recurrences in the cervical nodes are reported for NKTCLs (2.4%) than are reported for T-cell (10%) and B-cell (14.3%) malignancies.

Hemophagocytic syndrome, associated with fever, marked pancytopenia, hemophagocytic histiocytes in the bone marrow, and rapid liver function deterioration, is a devastating complication of NHL. This syndrome appears to be much more common in NKTCLs.

In a study involving 69 patients with early-stage extranodal nasal-type NKTCL (58 with stage I and 11 with stage II) who received primary radiotherapy, high pretreatment Epstein-Barr virus (EBV)-DNA concentrations were associated with B symptoms, elevated lactic dehydrogenase (LDH) levels and a high International Prognostic Index score. [9] The investigators suggested that circulating EBV-DNA levels could serve both as a valuable biomarker of tumor load for accurate classification of early-stage disease and as a prognostic factor.

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