NK-Cell Lymphomas of the Head and Neck 

The natural killer (NK) cell is a cytolytic cell that is an important component of the body's immune system. These cells are capable of conducting immune surveillance for tumorous, bacterial, and viral invaders. NK-cell lymphoma is a type of non-Hodgkin lymphoma (NHL). Most NHLs (90%) are B cell in origin. In the past, the rarity of non–B-cell malignancies and their similar morphologic findings coupled with the previous unavailability of cell markers led to the inability to classify 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 prognosis. This lack of knowledge is also demonstrated in previous classification systems, including the Lukes-Collins, Kiel, and Working Formulation systems, which did not identify subclasses of NK-/T-cell malignancies.

Recent advances in tumor cell biology have led to the ability to subclassify NHL via the World Health Organization (WHO) classification of lymphomas. 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 whether the malignancy represents the presence of a T cell with abnormal cell markers is under debate. This controversy has led many investigators to use the term NK-/T-cell lymphoma when classifying NK-cell lymphomas because of the absence of unequivocal proof of the exact lineage of these neoplasms. Further understanding of the development and identification of more specific cell markers of the NK cells and T cells will likely resolve this controversy in the future.

Peripheral T- and NK-cell lymphomas classified by the WHO have many subclasses (see World Health Organization classification of lymphomas). The subgroupings, which primarily involve the head and neck region, include the nasal and nasal-type extranodal NK-/T-cell lymphomas. The term extranodal is used because these forms of malignancies are found outside of the traditional lymph node groupings. The nasal and nasal-type NK-/T-cell lymphomas have distinct presentations and prognoses, and they are believed to have different pathogeneses. Otolaryngologists should understand the importance of differentiating NK-/T-cell lymphoma from other similar pathologic entities found in the head and neck region, as the prognosis is greatly affected.

World Health Organization classification of lymphomas

• B-cell neoplasms

  • 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-lymphoma)
  • Follicular lymphoma
  • Mantle cell lymphoma
  • Diffuse large B-cell lymphoma
  • Intravascular large B-cell lymphoma
• B-cell proliferations of uncertain malignant potential

  • Lymphomatoid granulomatosis
  • Posttransplant lymphoproliferative disorder, polymorphic
• T-cell and NK-cell neoplasms

  • Precursor T-lymphoblastic leukemia/lymphoma
  • Blastic NK-cell lymphoma
  • Adult T-cell leukemia/lymphoma
  • Extranodal NK-/T-cell lymphoma, 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 proliferation of uncertain malignant potential

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

Extranodal nasal NK-/T-cell lymphoma manifests in the nasal cavity. Patients with this type tend to have earlier disease (stage I). However, later-stage presentations are observed and have an impact on survival rate. Nasal NK-/T-cell lymphomas 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 elucidated.

Extranodal nasal-type NK-/T-cell lymphoma demonstrates predilection for the nasopharynx, palate, skin, soft tissues, orbit, gastrointestinal 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 the 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, gastrointestinal tract, and testes expressing the CD56 marker in large amounts, the neoplastic cells travel to these areas and set up foci of disease. Skin is the most common site of dissemination in NK-/T-cell lymphomas.

Frequency

United States

These lymphomas are very rare in whites. Prevalence is higher in people of Asian descent than in whites. 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.

International

Prevalence continues to be low, but this lymphoma is much more prevalent in Asia, Mexico, and Central and South America. Rates of nasal lymphoma in Hong Kong and South America have been reported to range from 2.6-8% of all NHLs, of which 45% are thought to represent NK-/T-cell lymphoma.

Mortality/Morbidity

When compared with other subtypes of lymphoma found in the head and neck region, NK-/T-cell lymphoma carries a much higher mortality rate and a decreased response to traditional chemotherapy and radiation therapy regimens. 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 rate is reported at 31%. Poor survival rates and response rates 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 because of its binding properties.

NK-/T-cell lymphoma has a higher local relapse rate (21.4%) than that of 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 (2.4%) than those 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 NHLs. This syndrome appears to be much more common in NK-/T-cell malignancies.

Sex

Men are more commonly affected with the disease than women, with a male-to-female ratio of almost 3:1.^{[1, 2]}

Age

Patients with NK-/T-cell lymphoma commonly present in their sixth decade of life, which is almost a decade younger than people with B-cell neoplasms present. However, the disease has been seen in both the geriatric and pediatric populations.^{[1, 2]}