NK-Cell Lymphomas of the Head and Neck
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.  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.
In the WHO lymphoma classification, B-cell neoplasms include the following:
Precursor B-lymphoblastic leukemia/lymphoma
Chronic lymphocytic leukemia/small lymphocytic lymphoma
Plasma cell myeloma
Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)
Mantle cell lymphoma
Diffuse large B-cell lymphoma
Intravascular large B-cell lymphoma
B-cell proliferations of uncertain malignant potential include the following:
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
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:
Histiocytic and dendritic-cell neoplasms
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, 3, 4]
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.
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.
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
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. [5, 6, 7] 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. [8, 9] Men are more commonly affected with the disease than women, with a male-to-female ratio of almost 3:1. [8, 9, 6]
Using the Surveillance, Epidemiology, and End Results (SEER) Program database, Kommalapati et al determined that between 2001 and 2014, the US incidence of nasal NKTCL doubled, from 0.4 to 0.8 per 1,000,000 individuals. The incidence in Hispanic patients was significantly higher than that in non-Hispanic patients. 
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.  Overall, median survival time is reported as 12.5 months (although the aforementioned study by Kommalapati et al reported the median overall survival time for nasal NKTCL to be 20 months, with this period varying significantly with the disease’s primary site and NKTCL’s stage at diagnosis  ). 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%.
A retrospective study by Su et al of 101 patients with extranodal NKTCL indicated that age 60 years or greater and the presence of Ann Arbor stage III/IV disease are independent risk factors for poor progression-free and overall survival. Median periods of progression-free and overall survival in the advanced-stage patients were 2.3 and 4.8 months, respectively. 
The poor survival rates and low rates of response to treatment in NKTCL 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. 
On the other hand, a literature review by Chen et al indicated that the prognosis in extranodal NKTCL tends to be better when CD30, a tumor necrosis factor receptor superfamily member, is expressed. The investigators reported that CD30 expression is associated with a 41% relative decrease in hazard of death. 
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.  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.
Similarly, a literature review by Liu et al indicated that in patients with NKTCL, circulating EBV-DNA concentrations predict patient survival and treatment response. The investigators reported that overall and progression-free survival are poorer in individuals with both a high pretreatment EBV-DNA level and a detectable posttreatment concentration. Moreover, an apparent association was found between a high pretreatment level and a decreased treatment response. 
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Benjamin Daniel Liess, MD Assistant Professor, Department of Otolaryngology, University of Missouri-Columbia School of Medicine
Benjamin Daniel Liess, MD is a member of the following medical societies: American Academy of Otolaryngic Allergy, American Academy of Otolaryngology-Head and Neck Surgery, The Triological Society, American Medical Association, Missouri State Medical Association
Disclosure: Nothing to disclose.
Jerry W Templer, MD Professor, Department of Otolaryngology, University of Missouri-Columbia School of Medicine
Jerry W Templer, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, Missouri State Medical Association, Society of University Otolaryngologists-Head and Neck Surgeons
Disclosure: Nothing to disclose.
Arlen D Meyers, MD, MBA Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine
Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;Cliexa;Preacute Population Health Management;The Physicians Edge<br/>Received income in an amount equal to or greater than $250 from: The Physicians Edge, Cliexa<br/> Received stock from RxRevu; Received ownership interest from Cerescan for consulting; for: Rxblockchain;Bridge Health.
Benoit J Gosselin, MD, FRCSC Associate Professor of Surgery, Dartmouth Medical School; Director, Comprehensive Head and Neck Oncology Program, Norris Cotton Cancer Center; Staff Otolaryngologist, Division of Otolaryngology-Head and Neck Surgery, Dartmouth-Hitchcock Medical Center
Benoit J Gosselin, MD, FRCSC is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society, American Medical Association, American Rhinologic Society, Canadian Medical Association, Canadian Society of Otolaryngology-Head & Neck Surgery, College of Physicians and Surgeons of Ontario, New Hampshire Medical Society,North American Skull Base Society, and Ontario Medical Association
Disclosure: Nothing to disclose.
M Sherif Said, MD, PhD Associate Professor of Pathology, Director of Head and Neck Pathology, Department of Pathology, University of Colorado School of Medicine
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
The authors would like to acknowledge Young S Paik, MD, for his assistance in the preparation and review of this manuscript.
NK-Cell Lymphomas of the Head and Neck
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